Process for preparing substituted pyridines

ABSTRACT

A process for preparing a compound of the formula  
                 
 
     wherein n, R 1 , R 2 , R 3  and X are as defined above, used as an intermediate in the synthesis of β-adrenergic receptor agonists.

CROSS REFERENCE TO RELATED APPLICATION

[0001] This application is a divisional of U.S. non-provisionalapplication Ser. No. 09/820,137, filed Mar. 28, 2001, now allowed, whichclaims priority from U.S. provisional application No. 60/193,772, filedMar. 31, 2000.

BACKGROUND OF THE INVENTION

[0002] The present invention relates to a process for preparingsubstituted pyridines which are intermediates in the synthesis ofβ-adrenergic receptor agonists useful as hypoglycemic and antiobesityagents, increasing lean meat deposition and/or improving the lean meatto fat ratio in edible animals. The β-adrenergic receptor agonistsfurther possess utility in the treatment of intestinal motility diseasedisorders, depression, prostate disease, dyslipidemia and airwayinflammatory disorders such as asthma and obstructive lung disease.

[0003] The disease diabetes mellitus is characterized by metabolicdefects in production and/or utilization of carbohydrates which resultin the failure to maintain appropriate blood sugar levels. The result ofthese defects is elevated blood glucose or hyperglycemia. Research inthe treatment of diabetes has centered on attempts to normalize fastingand postprandial blood glucose levels. Current treatments includeadministration of exogenous insulin, oral administration of drugs anddietary therapies.

[0004] Two major forms of diabetes mellitus are recognized. Type Idiabetes, or insulin-dependent diabetes, is the result of an absolutedeficiency of insulin, the hormone which regulates carbohydrateutilization. Type II diabetes, or non-insulin dependent diabetes, oftenoccurs with normal, or even elevated levels of insulin and appears to bethe result of the inability of tissues to respond appropriately toinsulin. Most of the Type II diabetics are also obese.

[0005] The β-adrenergic receptor agonists effectively lower bloodglucose levels when administered orally to mammals with hyperglycemia ordiabetes.

[0006] The β-adrenergic receptor agonists also reduce body weight ordecrease weight gain when administered to mammals. The ability ofa-adrenergic receptor agonists to affect weight gain is due toactivation of R-adrenergic receptors which stimulate the metabolism ofadipose tissue.

[0007] β-Adrenergic receptors have been categorized into β₁-, β₂- andβ₃-subtypes. Agonists of β-receptors promote the activation of adenylcyclase. Activation of β₁-receptors invokes increases in heart ratewhile activation of β₂-receptors induces relaxation of skeletal muscletissue which produces a drop in blood pressure and the onset of smoothmuscle tremors. Activation of β₃-receptors is known to stimulatelipolysis (the breakdown of adipose tissue triglycerides to glycerol andfree fatty acids) and metabolic rate (energy expenditure), and therebypromote the loss of fat mass. Compounds that stimulate β-receptors are,therefore, useful as anti-obesity agents, and can also be used toincrease the content of lean meat in edible animals. In addition,compounds which are β₃-receptor agonists have hypoglycemic and/oranti-diabetic activity, but the mechanism of this effect is unknown.

[0008] Until recently β₃-adrenergic receptors were thought to be foundpredominantly in adipose tissue. β₃-Receptors are now known to belocated in such diverse tissues as the intestine (J. Clin. Invest., 91,344 (1993)) and the brain (Eur. J. Pharm., 219,193 (1992)). Stimulationof β₃-receptors have been demonstrated to cause relaxation of smoothmuscle in colon, trachea and bronchi. Life Sciences, 44(19), 1411(1989); Br. J. Pharm., 112, 55 (1994); Br J. Pharmacol, 110, 1311(1993). For example, stimulation of β₃-receptors has been found toinduce relaxation of histamine-contracted guinea pig ileum, J. Pharm.Exp. Ther., 260, 1, 192 (1992).

[0009] The β₃-receptor is also expressed in human prostate. Becausestimulation of β₃-receptors cause relaxation of smooth muscles that havebeen shown to express the ⊖₃-receptor (e.g. intestine), one skilled inthe art would predict relaxation of prostate smooth muscle. Therefore,β₃-agonists will be useful for the treatment or prevention of prostatedisease.

SUMMARY OF THE INVENTION

[0010] The present invention relates to a process for preparing acompound of the formula

[0011] wherein n is 0, 1, 2 or 3;

[0012] R¹ is hydrogen or halo;

[0013] each R² is independently hydrogen, halo, trifluoromethyl, cyano,SR⁴, OR⁴, SO₂R⁴, OCOR⁵, or (C₁-C₁₀)alkyl wherein the alkyl group isoptionally substituted by hydroxy, halo, cyano, N(R⁴)₂, SR⁴,trifluoromethyl, OR⁴, (C₃-C₈)cycloalkyl, (C₆-C₁₀)aryl, NR⁴COR⁵, COR⁵,SO₂R⁵, OCOR⁵, NR⁴SO₂R⁵ or NR⁴CO₂ R⁴;

[0014] R³ is tetrahydrofuranyl, tetrahydropyranyl or a silyl protectinggroup;

[0015] X is halo, methanesulfonyloxy, benzenesulfonyloxy,p-toluenesulfonyloxy, m-nitrobenzenesulfonyloxy orp-nitrobenzenexulfonyloxy;

[0016] R⁴ and R⁵, for each occurrence, are each independently selectedfrom hydrogen, (C₁-C₁₀)alkyl, (C₁-C₁₀)alkoxy,(C₃-C₈)cycloalkyl,(C₆-C₁₀)aryl, (C₂-C₉)heterocycloalkyl,(C₂-C₉)heteroaryl or (C₁-C₆)aryl wherein the alkyl group is optionallysubstituted by the group consisting of hydroxy, halo, carboxy,(C₁-C₁₀)alkyl-CO₂, (C₁-C₁₀)alkylsulfonyl, (C₃-C₈)cycloalkyl,(C₁-C₁₀)alkoxy, or (C₁-C₆)alkyl; and wherein the aryl, heterocycloalkyland heteroaryl groups are optionally substituted by one to four groupsconsisting of halo, nitro, oxo, ((C₁-C₆)alkyl)₂amino, pyrrolidine,piperidine, (C₁-C₁₀)alkyl, (C₁-C₁₀)alkoxy, (C₁-C₁₀)alkylthio and(C₁-C₁₀)alkyl wherein the alkyl group is optionally substituted by oneto four groups selected from hydroxy, halo, carboxy, (C₁-C₆)alkyl-CO₂,(C₁-C₆)alkylsulfonyl, (C₃-C₈)cycloalkyl and (C₁-C₆)alkoxy;

[0017] or R⁵ is N(R⁴)₂ wherein R⁴ is as defined above;

[0018] comprising reacting a compound of the formula

[0019] wherein n, R¹, R² and X are as defined above, with a silyatingagent in the presence of a base.

[0020] The term “alkyl”, as used herein, as well as the alkyl moietiesof other groups referred to herein (e.g., alkoxy), may be linear orbranched, and they may also be cyclic (e.g., cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or cycloheptyl) or be linear or branched andcontain cyclic moieties. Unless otherwise indicated, halogen includesfluorine, chlorine, bromine, and iodine.

[0021] The term “halo”, as used herein, unless otherwise indicated,includes fluoro, chloro, bromo or iodo.

[0022] (C₂-C₉)Heterocycloalkyl when used herein includes, but is notlimited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl,tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, oxiranyl,methylenedioxyl, chromenyl, barbituryl, isoxazolidinyl,1,3-oxazolidin-3-yl, isothiazolidinyl, 1,3-thiazolidin-3-yl,1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, piperidinyl,thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-3-yl,tetrahydrothiadiazinyl, morpholinyl, 1,2-tetrahydrodiazin-2-yl,1,3-tetrahydrodiazin-1-yl, tetrahydroazepinyl, piperazinyl, chromanyl,etc.

[0023] (C₂-C₉)Heteroaryl when used herein includes, but is not limitedto, furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl,isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl,1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl,1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl,1,3,5-triazinyl, pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridinyl,purinyl, 6,7-dihydro-5H-[1]pyrindinyl, benzo[b]thiophenyl, 5,6,7,8-tetrahydro-quinolin-3-yl, benzoxazolyl, benzothiazolyl,benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl,isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl,indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl,quinoxalinyl, quinazolinyl, benzoxazinyl, etc.

[0024] The term “silyl protecting group”, when used herein includes, butis not limited to, trimethylsilyl, triethylsilyl, triisopropylsilyl,dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl,t-butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl,tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl, andt-butylmethoxyphenylsilyl.

[0025] The present invention further relates to a process wherein thesilyating agent is tert-butyldimethylsilyl chloride,triethylchlorosilane, triisopropylchlorosilane ordiphenylmethylchlorosilane.

[0026] The present invention further relates to a process wherein thebase is triethylamine, N,N-diisopropylethylamine, imidazole, pyridine,2,6-lutidine or N-methylmorpholine.

[0027] The present invention further relates to a process wherein thecompound of the formula

[0028] is formed by reacting a compound of the formula

[0029] wherein n, R¹ and R² are as defined above, with a sulfonylchloride in the presence of a base, and in the case wherein X is halo,by further treatment with a metal halide.

[0030] The present invention further relates to a process wherein thesulfonyl chloride is p-toluenesulfonyl chloride, methanesulfonylchloride, m-nitrobenzenesulfonyl chloride, p-nitrobenzenesulfonylchloride or benezenesulfonyl chloride.

[0031] The present invention further relates to a process wherein thebase is triethylamine, diisopropylethylamine, pyridine, 2,4,6-collidineor 2,6-lutidine.

[0032] The present invention further relates to a process wherein themetal halide is lithium chloride.

[0033] The present invention further relates to a process wherein thecompound of the formula

[0034] is formed by reacting a compound of the formula

[0035] wherein n, R¹ and R² are as defined above, with a dihydroxylatingagent, with or without a co-oxidant and/or a coordinating ligand.

[0036] The present invention further relates to a process wherein thedihydroxylating agent is osmium tetroxide or potassium permanganate.

[0037] The present invention further relates to a process wherein theco-oxidant is potassium ferricyanide, hydrogen peroxide, tert-butylhydroperoxide or N-methylmorpholine-N-oxide.

[0038] The present invention further relates to a process wherein thecoordinating ligand is hydroquinidine 1,4-phthalazinediyl diether orhydroquinine 1,4-phthalazinediyl diether.

[0039] The present invention further relates to a process wherein thecompound of the formula

[0040] is formed by reacting a compound of formula V

[0041] wherein n, R¹ and R² are as defined above, with a methylatingreagent.

[0042] The present invention further relates to a process wherein themethylating reagant is prepared from methyltriphenylphosphonium bromideand potassium tert-butoxide.

[0043] The present invention further relates to a process wherein thecompound of the formula

[0044] is formed by reducing a compound of the formula

[0045] wherein n, R¹ and R² are as defined above, with a reducing agentfollowed by hydrolysis with an acid or base.

[0046] The present invention further relates to a process wherein thereducing agent is diisobutylaluminum hydride.

[0047] The present invention further relates to a process wherein theacid is sulfuric acid.

[0048] The present invention relates to a process for preparing acompound of the formula

[0049] wherein n is 0, 1, 2 or 3;

[0050] R¹ is hydrogen or halo;

[0051] each R² is independently hydrogen, halo, trifluoromethyl, cyano,SR⁴, OR⁴, SO₂R⁴, OCOR⁵, or (C₁-C₁₀)alkyl wherein the alkyl group isoptionally substituted by hydroxy, halo, cyano, N(R⁴)₂, SR⁴,trifluoromethyl, OR⁴, (C₃-C₈)cycloalkyl, (C₆-C₁₀)aryl, NR⁴COR⁵, COR⁵,SO₂R⁵, OCOR⁵, NR⁴SO₂R⁵ and NR⁴CO₂ R⁴;

[0052] R³ is tetrahydrofuranyl, tetrahydropyranyl or a silyl protetctinggroup;

[0053] X is halo, methanesulfonyloxy, benzenesulfonyloxy,p-toluenesulfonyloxy, m-nitrobenzenesulfonyloxy orp-nitrobenzenexulfonyloxy;

[0054] R⁴ and R⁵ are each independently selected from hydrogen,(C₁-C₁₀)alkyl, (C₁-C₁₀)alkoxy,(C₃-C₈)cycloalkyl,(C₆-C₁₀)aryl,(C₂-C₉)heterocycloalkyl, (C₂-C₉)heteroaryl or (C₁-C₆)aryl wherein thealkyl group is optionally substituted by the group consisting ofhydroxy, halo, carboxy, (C₁-C₁₀)alkyl-CO₂, (C₁-C₁₀)alkylsulfonyl,(C₃-C₈)cycloalkyl, (C₁-C₁₀)alkoxy, or (C₁-C₆)alkyl; and wherein thearyl, heterocycloalkyl and heteroaryl groups are optionally substitutedby one to four groups consisting of halo, nitro, oxo,((C₁-C₆)alkyl)₂amino, pyrrolidine, piperidine, (C₁-C₁₀)alkyl,(C₁-C₁₀)alkoxy, (C₁-C₁₀)alkylthio and (C₁-C₁₀)alkyl wherein the alkylgroup is optionally substituted by one to four groups selected fromhydroxy, halo, carboxy, (C₁-C₆)alkyl-CO₂, (C₁-C₆)alkylsulfonyl,(C₃-C₈)cycloalkyl or (C₁-C₆)alkoxy;

[0055] or R⁵ is N(R⁴)₂ wherein R⁴ is as defined above; and

[0056] comprising (a) reacting a compound of the formula

[0057] wherein n, R¹ and R² as defined above, with a reducing agentfollowed by hydrolsis with an acid or base;

[0058] (b) reacting the intermediate of formula XIII so formed

[0059] wherein n, R¹ and R² are as defined above, with a methylatingagent to form a vinylpyridine compound of the formula

[0060] (c) reacting the vinylpyridine compound so formed in step (b)with a dihydroxylating agent, with or without a co-oxidant and/or acoordinating ligand to form a compound of the formula

[0061] wherein n, R¹ and R² are as defined above;

[0062] (d) reacting the compound of formula XI so formed with a sulfonylchloride in the presence of a base to form a compound of the formula X

[0063] wherein n, R¹, R² and X are as defined above; and

[0064] (e) reacting the compound of formula X so formed with silyatingagent in the presence of a base.

[0065] The present invention relates to a process for preparing acompound of the formula

[0066] wherein n is 0, 1, 2 or 3;

[0067] each R² is independently hydrogen, halo, trifluoromethyl, cyano,SR⁴, OR⁴, SO₂R⁴, OCOR⁵, or (C₁-C₁₀)alkyl wherein the alkyl group isoptionally substituted by hydroxy, halo, cyano, N(R⁴)₂, SR⁴,trifluoromethyl, OR⁴, (C₃-C₈)cycloalkyl, (C₆-C₁₀)aryl, NR⁴COR⁵, COR⁵,SO₂R⁵, OCOR⁵, NR⁴SO₂R⁵ or NR⁴CO₂ R⁴;

[0068] R⁴ and R⁵, for each occurrence, are each independently selectedfrom hydrogen, (C₁-C₁₀)alkyl, (C₁-C₁₀)alkoxy,(C₃-C₈)cycloalkyl,(C₆-C₁₀)aryl, (C₂-C₉)heterocycloalkyl,(C₂-C₉)heteroaryl or (C₁-C₆)aryl wherein the alkyl group is optionallysubstituted by the group consisting of hydroxy, halo, carboxy,(C₁-C₁₀)alkyl-CO₂, (C₁-C₁₀)alkylsulfonyl, (C₃-C₈)cycloalkyl,(C₁-C₁₀)alkoxy, or (C₁-C₆)alkyl; and wherein the aryl, heterocycloalkyland heteroaryl groups are optionally substituted by one to four groupsconsisting of halo, nitro, oxo, ((C₁-C₆)alkyl)₂amino, pyrrolidine,piperidine, (C₁-C₁₀)alkyl, (C₁-C₁,)alkoxy, (C₁-C₁₀)alkylthio and(C₁-C₁₀)alkyl wherein the alkyl group is optionally substituted by oneto four groups selected from hydroxy, halo, carboxy, (C₁-C₆)alkyl-CO₂,(C₁-C₆)alkylsulfonyl, (C₃-C₈)cycloalkyl and (C₁-C₆)alkoxy;

[0069] or R⁵ is N(R⁴)₂ wherein R⁴ is as defined above;

[0070] R⁶ is COR⁷ or CO₂R⁷ wherein R⁷ is (C₁-C₈)alkyl; and

[0071] Y is

[0072] wherein:

[0073] Q¹ is oxygen, nitrogen or sulfur;

[0074] Q² is carbon or nitrogen;

[0075] Q³ is hydrogen, —(CH₂)_(q)-phenyl, —(C₁-C₁₀)alkyl,—(CH₂)_(q)—NG¹G², —(CH₂)_(q)—CO₂G³, (CH₂)_(q)—CO-NG¹G², (CH₂)_(q)—OG³,—(CH₂)_(q)SO₃G³, —(CH₂)_(q)—SO₂—(C₁-C₆)alkyl, —(CH₂)_(q)—SO₂NG¹G², or aheterocycle selected from the group consisting of —(CH₂)_(q)-pyridyl,—(CH₂)_(q)-pyrimidyl, —(CH₂)_(q)-pyraziqyl, —(CH₂)_(q)-isoxazolyl,(CH₂)_(q)-oxazolyl, —(CH₂)_(q)-thiazolyl,—(CH₂)_(q)-(1,2,4-oxadiazolyl), —(CH₂)_(q)-imidazolyl,—(CH₂)_(q)-triazolyl and —(CH₂)_(q)-tetrazolyl;

[0076] wherein one of the ring nitrogen atoms of said—(CH₂)_(q)-imidazolyl, —(CH₂)_(q)-triazolyl and —(CH₂)_(q)-tetrazolylmay optionally be substituted by (C₁-C₈)alkyl optionally independentlysubstituted with one or more halo atoms;

[0077] wherein each of said heterocycles may optionally be substitutedon one or more of the ring carbon atoms by one or more substituentsindependently selected from the group consisting of (C₁-C₈)alkyloptionally independently substituted with one or more halo atoms, nitro,cyano, —(CH₂)_(q)—NG¹G², —(CH₂)_(q)—CO₂G³, —(CH₂)_(q)—CO—NG¹G²,—(CH₂)_(q)—OG³, —(CH₂)_(q)—SO₃G³, —(CH₂)_(q)—SO₂—(C₁-C₆)alkyl and—(CH₂)_(q)—SO₂NG¹G²;

[0078] wherein the phenyl moiety of said —(CH₂)_(q)-phenyl mayoptionally be substituted with one or more substituents independentlyselected from the group consisting of (C₁-C₆)alkyl optionallyindependently substituted with one or more halo atoms, hydroxy,(C₁-C₆)alkoxy optionally independently substituted with one or more haloatoms, (C₁-C₆)alkylthio, fluoro, chloro, bromo, iodo, cyano, nitro,—(CH₂)_(q)—NG¹G², —(CH₂)_(q)—CO₂G³, —(CH₂)_(q)—CO-NG¹G², —(CH₂)_(q)—OG³,(CH₂)_(q)SO₃G³, (CH₂)_(q)SO₂(C₁-C₆)alkyl, —(CH₂)_(q)—SO₂NG¹G²;—(CH₂)_(q)—NG³_SO₂-G³ and —(CH₂)_(q)—NG³—SO₂—NG¹G²; Q⁴ is —(CH₂)_(q)—CN,—(CH₂)_(q)CO₂G³, —(CH₂)_(q)—SO₃G³, —(CH₂)_(q)—SO₂-(C₁-C₆)alkyl,—(CH₂)_(q)SO₂NG¹G², —(CH₂)_(q)CH₂OH, (CH₂)_(q)CHO, (CH₂)_(q)CO-G³,—(CH₂)_(q)—CONG¹G², or a heterocycle selected from —(CH₂)_(q)-thiazolyl,—(CH₂)_(q)-oxazolyl, —(CH₂)_(q)-imidazolyl, —(CH₂)_(q)-triazolyl,—(CH₂)_(q)-1,2,4-oxadiazolyl, —(CH₂)_(q)-isoxazolyl,—(CH₂)_(q)-tetrazolyl and —(CH₂)_(q)-pyrazolyl;

[0079] wherein one of the ring nitrogen atoms of said—(CH₂)_(q)-imidazolyl, —(CH₂)_(q)-triazolyl and —(CH₂)_(q)-tetrazolylmay optionally be substituted by (C₁-C₆)alkyl optionally independentlysubstituted with one or more halo atoms;

[0080] wherein each of said heterocycles may optionally be substitutedon one or more of the ring carbon atoms by one or more substituentsindependently selected from the group consisting of hydrogen,(C₁-C₆)alkyl optionally independently substituted with one or more haloatoms, —(CH₂)_(q)—CO-NG¹G², —(CH₂)_(q)—CO₂G³, halo, nitro, cyano,—(CH₂)_(q)—CO-NG¹G², —(CH₂)_(q)—OG³, —(CH₂)_(q)—SO₃G³,(CH₂)_(q)SO₂—(C₁-C₆)alkyl, or —(CH₂)_(q)—SO₂NG¹G²;

[0081] Q⁵ is hydrogen or (C₁-C₆)alkyl optionally independentlysubstituted with one or more halo atoms;

[0082] Q⁶ is a covalent bond, oxygen or sulfur;

[0083] Q⁷ is hydrogen or (C₁-C₆)alkyl optionally independentlysubstituted with one or more halo atoms;

[0084] Q⁸ and Q⁹ are independently a covalent bond, oxygen, sulfur, NHor N-(C₁-C₆)alkyl;

[0085] Q¹⁰ is nitro, amino, (C₂-C₉)heteroaryl, (C₂-C₉)heterocycloalkyl,(CH₂)_(p)OR¹¹, (CH₂)_(q)CO₂H, (CH₂)_(q)COR¹³, (CH₂)_(q)SO₂NR¹¹ R¹²,(CH₂)_(q)N R¹¹ SO₂R¹⁰, (CH₂)_(q)P(O)(OR⁸)(OR⁹),(CH₂)_(q)—O—(CH₂)_(p)CO₂H, (CH₂)_(q)—O—(CH₂)_(p)COR¹³,(CH₂)_(q)—O—(CH₂)_(p)P(O)(OR⁸)(OR⁹), (CH₂)_(q)—O—(CH₂)_(p)SO₂NR¹¹R¹², or(CH₂)_(q)O(CH₂)_(p)—NR¹¹SO₂R¹⁰;

[0086] R⁸ and R⁹ are each independently hydrogen or (C₁-C₆)alkyl; and

[0087] wherein G¹ and G² for each occurrence are each independentlyhydrogen, (C₁-C₆)alkyl optionally independently substituted with one ormore halo, (C₁-C₈)alkoxy(C₁-C₆)alkyl or (C₃-C₈)cycloalkyl, or G¹ and G²together with the nitrogen to which they are attached form a saturatedheterocyclic ring having from 3 to 7 carbon atoms wherein one of saidcarbon atoms may optionally be replaced by oxygen, nitrogen or sulfur;

[0088] G³ for each occurrence is independently hydrogen or (C₁-C₆)alkyl;

[0089] R¹⁰ for each occurrence is independently (C₁-C₆)alkyl or(C₁-C₆)alkoxy(C₁-C₆)alkyl;

[0090] R¹¹ and R¹² are taken separately and, for each occurrence, areindependently hydrogen, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, or(C₁-C₆)alkoxy(C₁-C₆)alkyl, or R¹¹ and R¹² are taken together with thenitrogen atom to which they are attached and form a pyrrolidine,piperidine or morpholine ring wherein said pyrrolidine, piperidine ormorpholine may optionally be substituted at any carbon atom by(C₁-C₄)alkyl or (C₁-C₄)alkoxy;

[0091] R¹³ for each occurrence is independently hydrogen, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, NR¹¹R¹², (C₃-C₈)cycloalkyl, or (C₁-C₆)alkoxy(C₁-C₆)alkylwherein R¹¹ and R¹² are as defined above;

[0092] R¹⁴ and R¹⁵ are each independently hydrogen, halo, (C₁-C₆)alkyl,nitro, cyano, trifluoromethyl, SO₂R¹⁰, SO₂NR¹¹R¹², NR¹¹R¹², COR¹³,CO₂R¹¹, (C₁-C₆)alkoxy, NR¹¹SO₂R¹⁰, NR¹¹COR¹³, NR¹¹CO₂R¹¹ or OR¹¹;

[0093] p for each occurrence is independently an integer of 1 to 6; and

[0094] q for each occurrence is independently 0 or an integer of 1 to 6;

[0095] with the proviso that when Q⁹ is O or S then n is not 0;

[0096] with the proviso that when Q¹ is oxygen or sulfur then Q³ isabsent; and

[0097] with the proviso that when Q² is nitrogen then Q⁵ is absent;

[0098] comprising reacting a compound of the formula

[0099] wherein n, R², R⁶ and Y are as defined above; and R³ istetrahydrofuranyl, tetrahydropyranyl or a silyl protetcting group; withtetra-n-butylammonium fluoride.

[0100] The present invention further relates to a process wherein acompound of the formula

[0101] wherein n, R², R³, R⁶ and Y are as defined above, is formed bytreating a compound of the formula

[0102] wherein R¹ is halo and wherein n, R², R³, R⁶ and Y are as definedabove, with ammonium formate in the presence of palladium on carbon.

[0103] The present invention further relates to a process wherein acompound of the formula

[0104] is formed by reacting a compound of the formula

[0105] wherein R¹ is hydrogen or halo and wherein n, R², R³ and Y are asdefined above with an organic acid anhydride, a dicarbonate or anorganic acid chloride.

[0106] The present invention further relates to a process wherein thedicarbonate is di-tert-butyl dicarbonate

[0107] The present invention further relates to a process wherein acompound of the formula

[0108] is formed by reacting the compound

[0109] wherein n, R¹, R², R³ and X are as defined above, with an amineof the formula H₂NY, wherein Y is as defined above, in the presence ofN,N-diisopropylethylamine.

[0110] The present invention relates to a process for preparing acompound of the formula

[0111] wherein n is 0, 1, 2 or 3;

[0112] each R² is independently hydrogen, halo, trifluoromethyl, cyano,SR⁴, OR⁴, SO₂R⁴, OCOR⁵, or (C₁-C₁₀)alkyl wherein the alkyl group isoptionally substituted by hydroxy, halo, cyano, N(R⁴)₂, SR⁴,trifluoromethyl, OR⁴, (C₃-C₈)cycloalkyl, (C₆-C₁₀)aryl, NR⁴COR⁵, COR⁵,SO₂R⁵, OCOR⁵, NR⁴SO₂R⁵ and NR⁴CO₂ R⁴;

[0113] R⁴ and R⁵, for each occurrence, are each independently selectedfrom hydrogen, (C₁-C₁₀)alkyl, (C₁-C₁₀)alkoxy,(C₃-C₈)cycloalkyl,(C₆-C₁₀)aryl, (C₂-C₉)heterocycloalkyl,(C₂-C₉)heteroaryl or (C₁-C₆)aryl wherein the alkyl group is optionallysubstituted by the group consisting of hydroxy, halo, carboxy,(C₁-C₁₀)alkyl-CO₂, (C₁-C₁₀)alkylsulfonyl, (C₃-C₈)cycloalkyl,(C₁-C₁₀)alkoxy, or (C₁-C₆)alkyl; and wherein the aryl, heterocycloalkyland heteroaryl groups are optionally substituted by one to four groupsconsisting of halo, nitro, oxo, ((C₁-C₆)alkyl)₂amino, pyrrolidine,piperidine, (C₁-C₁₀)alkyl, (C₁-C₁₀)alkoxy, (C₁-C₁₀)alkylthio and(C₁-C₁₀)alkyl wherein the alkyl group is optionally substituted by oneto four groups selected from hydroxy, halo, carboxy, (C₁-C₆)alkyl-CO₂,(C₁-C₆)alkylsulfonyl, (C₃-C₈)cycloalkyl and (C₁-C₆)alkoxy;

[0114] or R⁵ is N(R⁴)₂ wherein R⁴ is as defined above;

[0115] R⁶ is COR⁷ or CO₂R⁷ wherein R⁷ is (C₁-C₈)alkyl; and

[0116] Y is

[0117] wherein:

[0118] Q¹ is oxygen, nitrogen or sulfur;

[0119] Q² is carbon or nitrogen;

[0120] Q³ is hydrogen, —(CH₂)_(q)-phenyl, —(C₁-C₁₀)alkyl,—(CH₂)_(q)—NG¹G², —(CH₂)_(q)—CO₂G³, (CH₂)_(q)CO—NG¹G², (CH₂)_(q)OG³,—(CH₂)_(q)SO₃G³, —(CH₂)_(q)—SO₂—(C₁-C₆)alkyl, —(CH₂)_(q)—SO₂NG¹G², or aheterocycle selected from the group consisting of —(CH₂)_(q)-pyridyl,—(CH₂)_(q)-pyrimidyl, —(CH₂)_(q)-pyraziqyl, —(CH₂)_(q)-isoxazolyl,(CH₂)_(q) oxazolyl, —(CH₂)_(q)-thiazolyl, (CH₂)_(q)(1,2,4-oxadiazolyl),—(CH₂)_(q)-imidazolyl, —(CH₂)_(q)-triazolyl and —(CH₂)_(q)-tetrazolyl;

[0121] wherein one of the ring nitrogen atoms of said—(CH₂)_(q)-imidazolyl, —(CH₂)_(q)-triazolyl and —(CH₂)_(q)-tetrazolylmay optionally be substituted by (C₁-C₈)alkyl optionally independentlysubstituted with one or more halo atoms;

[0122] wherein each of said heterocycles may optionally be substitutedon one or more of the ring carbon atoms by one or more substituentsindependently selected from the group consisting of (C₁-C₈)alkyloptionally independently substituted with one or more halo atoms, nitro,cyano, —(CH₂)_(q)—NG¹G², —(CH₂)_(q)—CO₂G³, —(CH₂)_(q)—CO-NG¹G²,(CH₂)_(q)OG³, (CH₂)_(q)SO₃G³, —(CH₂)_(q)—SO₂-(C₁-C₆)alkyl and—(CH₂)_(q)—SO₂NG¹G²;

[0123] wherein the phenyl moiety of said —(CH₂)_(q)-phenyl mayoptionally be substituted with one or more substituents independentlyselected from the group consisting of (C₁-C₆)alkyl optionallyindependently substituted with one or more halo atoms, hydroxy,(C₁-C₆)alkoxy optionally independently substituted with one or more haloatoms, (C₁-C₆)alkylthio, fluoro, chloro, bromo, iodo, cyano, nitro,—(CH₂)_(q)—NG¹G², (CH₂)_(q)CO₂G³, (CH₂)_(q)CO-NG¹G², (CH₂)_(q)OG³,—(CH₂)_(q)—SO₃G³, (CH₂)_(q)SO₂(C₁-C₆)alkyl, —(CH₂)_(q)—SO₂NG¹G²;—(CH₂)_(q)—NG³, —SO₂-G³ and —(CH₂)_(q)—NG³_SO₂—NG¹G²; Q⁴ is—(CH₂)_(q)—CN, —(CH₂)_(q)CO₂G³, (CH₂)_(q)SO₃G³,—(CH₂)_(q)—SO₂-(C₁-C₆)alkyl, —(CH₂)_(q)—SO₂NG¹G², —(CH₂)_(q)CH₂OH,—(CH₂)_(q)—(CHO, —(CH₂)_(q)—CO-G³, —(CH₂)_(q)—CONG¹G², or a heterocycleselected from —(CH₂)_(q)-thiazolyl, —(CH₂)_(q)-oxazolyl,—(CH₂)_(q)-imidazolyl, —(CH₂)_(q)-triazolyl,—(CH₂)_(q)-1,2,4-oxadiazolyl, —(CH₂)_(q)-isoxazolyl,—(CH₂)_(q)-tetrazolyl and —(CH₂)_(q)-pyrazolyl;

[0124] wherein one of the ring nitrogen atoms of said—(CH₂)_(q)-imidazolyl, —(CH₂)_(q)-triazolyl and —(CH₂)_(q)-tetrazolylmay optionally be substituted by (C₁-C₆)alkyl optionally independentlysubstituted with one or more halo atoms;

[0125] wherein each of said heterocycles may optionally be substitutedon one or more of the ring carbon atoms by one or more substituentsindependently selected from the group consisting of hydrogen,(C₁-C₆)alkyl optionally independently substituted with one or more haloatoms, —(CH₂)_(q)—CO-NG¹G², —(CH₂)_(q)—CO₂G³, halo, nitro, cyano,—(CH₂)_(q)—CO-NG¹G², —(CH₂)_(q)—OG³, —(CH₂)_(q)—SO₃G³,(CH₂)_(q)SO₂(C₁-C₆)alkyl, or —(CH₂)_(q)—SO₂NG¹G²;

[0126] Q⁵ is hydrogen or (C₁-C₆)alkyl optionally independentlysubstituted with one or more halo atoms;

[0127] Q⁶ is a covalent bond, oxygen or sulfur;

[0128] Q⁷ is hydrogen or (C₁-C₆)alkyl optionally independentlysubstituted with one or more halo atoms;

[0129] Q⁸ and Q⁹ are independently a covalent bond, oxygen, sulfur, NHor N-(C₁-C₆)alkyl;

[0130] Q¹⁰ is nitro, amino, (C₂-C₉)heteroaryl, (C₂-C₉)heterocycloalkyl,(CH₂)_(p)OR¹¹, (CH₂)_(q)CO₂H, (CH₂)_(q)COR¹³, (CH₂)_(q)SO₂NR¹¹R¹²,(CH₂)_(q)NR¹¹SO₂R¹⁰, (CH₂)_(q)P(O)(OR⁸)(OR⁹), (CH₂)_(q)O(CH₂)_(p)CO₂H,(CH₂)_(q)—O—(CH₂)_(p)COR¹³, (CH₂)_(q)—(CH₂)_(p)P(O)(OR⁸)(OR⁹),(CH₂)_(q)—O—(CH₂)_(p)SO₂NR¹¹R¹², or (CH₂)_(q)—O—(CH₂)_(p)—NR¹¹SO₂R¹⁰;

[0131] R⁸ and R⁹ are each independently hydrogen or (C₁-C₆)alkyl; and

[0132] wherein G¹ and G² for each occurrence are each independentlyhydrogen, (C₁-C₆)alkyl optionally independently substituted with one ormore halo, (C₁-C₈)alkoxy(C₁-C₆)alkyl or (C₃-C₈)cycloalkyl, or G¹ and G²together with the nitrogen to which they are attached form a saturatedheterocyclic ring having from 3 to 7 carbon atoms wherein one of saidcarbon atoms may optionally be replaced by oxygen, nitrogen or sulfur;

[0133] G³ for each occurrence is independently hydrogen or (C₁-C₆)alkyl;

[0134] R¹⁰ for each occurrence is independently (C₁-C₆)alkyl or(C₁-C₆)alkoxy(C₁-C₆)alkyl;

[0135] R¹¹ and R¹² are taken separately and, for each occurrence, areindependently hydrogen, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, or(C₁-C₆)alkoxy(C₁-C₆)alkyl, or R¹¹ and R¹² are taken together with thenitrogen atom to which they are attached and form a pyrrolidine,piperidine or morpholine ring wherein said pyrrolidine, piperidine ormorpholine may optionally be substituted at any carbon atom by(C₁-C₄)alkyl or (C₁-C₄)alkoxy;

[0136] R¹³ for each occurrence is independently hydrogen, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, NR¹R¹², (C₃-C₈)cycloalkyl, or (C₁-C₆)alkoxy(C₁-C₆)alkylwherein R¹¹ and R¹² are as defined above;

[0137] R¹⁴ and R¹⁵ are each independently hydrogen, halo, (C₁-C₆)alkyl,nitro, cyano, trifluoromethyl, SO₂R¹⁰, SO₂NR¹¹R¹², NR¹¹R¹², COR¹³,CO₂R¹¹, (C₁-C₆)alkoxy, NR¹¹SO₂R¹⁰, NR¹¹COR¹³, NR¹¹CO₂R¹¹ or OR¹¹;

[0138] p for each occurrence is independently an integer of 1 to 6; and

[0139] q for each occurrence is independently 0 or an integer of 1 to 6;

[0140] with the proviso that when Q⁹ is O or S then n is not 0;

[0141] with the proviso that when Q¹ is oxygen or sulfur then Q³ isabsent; and

[0142] with the proviso that when Q² is nitrogen then Q⁵ is absent;

[0143] comprising (a) reacting a compound of the formula

[0144] wherein R¹ is hydrogen or halo, and n, R¹, R², R³ and X are asdefined above, with an amine of the formula H₂NY, wherein Y is asdefined above in the presence of N,N-diisopropylethylamine;

[0145] (b) reacting the compound of formula IV so formed

[0146] wherein R¹ is hydrogen or halo and wherein n, R², R³ and Y are asdefined above with an organic acid anhydride, a dicarbonate or anorganic acid chloride, to form a compound of the formula

[0147] (c) treating the compound of formula III, wherein R¹ is halo, soformed in step (b) with ammonium formate in the presence ofpalladium-on-carbon to form the compound of the formula

[0148] wherein n, R², R³, R⁶ and Y are as defined above, and

[0149] (d) treating the compound of formula II so formed withtetra-n-butylammonium fluoride.

[0150] The present invention relates to a process for preparing acompound of the formula

[0151] wherein n is 0, 1, 2 or 3;

[0152] each R² is independently hydrogen, halo, trifluoromethyl, cyano,SR⁴, OR⁴, SO₂R⁴, OCOR⁵, or (C₁-C₁₀)alkyl wherein the alkyl group isoptionally substituted by hydroxy, halo, cyano, N(R⁴)₂, SR⁴,trifluoromethyl, OR⁴, (C₃-C₈)cycloalkyl, (C₆-C₁₀)aryl, NR⁴COR⁵, COR⁵,SO₂R⁵, OCOR⁵, NR⁴SO₂R⁵ and NR⁴CO₂ R⁴;

[0153] R⁴ and R⁵, for each occurrence, are each independently selectedfrom hydrogen, (C₁-C₁₀)alkyl, (C₁-C₁₀)alkoxy,(C₃-C₈)cycloalkyl,(C₆-C₁₀)aryl, (C₂-C₉)heterocycloalkyl,(C₂-C₉)heteroaryl or (C₁-C₆)aryl wherein the alkyl group is optionallysubstituted by the group consisting of hydroxy, halo, carboxy,(C₁-C₁₀)alkyl-CO₂, (C₁-C₁₀)alkylsulfonyl, (C₃-C₈)cycloalkyl,(C₁-C₁₀)alkoxy, or (C₁-C₆)alkyl; and wherein the aryl, heterocycloalkyland heteroaryl groups are optionally substituted by one to four groupsconsisting of halo, nitro, oxo, ((C₁-C₆)alkyl)₂amino, pyrrolidine,piperidine, (C₁-C₁₀)alkyl, (C₁-C₁₀)alkoxy, (C₁-C₁₀)alkylthio and(C₁-C₁₀)alkyl wherein the alkyl group is optionally substituted by oneto four groups selected from hydroxy, halo, carboxy, (C₁-C₆)alkyl-CO₂,(C₁-C₆)alkylsulfonyl, (C₃-C₈)cycloalkyl and (C₁-C₆)alkoxy;

[0154] or R⁵ is N(R⁴)₂ wherein R⁴ is as defined above;

[0155] R⁶ is COR⁷ or CO₂R⁷ wherein R⁷ is (C₁-C₈)alkyl; and

[0156] Y is

[0157] wherein:

[0158] Q¹ is oxygen, nitrogen or sulfur;

[0159] Q² is carbon or nitrogen;

[0160] Q³ is hydrogen, —(CH₂)_(q)-phenyl, —(C₁-C₁₀)alkyl,—(CH₂)_(q)—NG¹G², —(CH₂)_(q)—CO₂G³, (CH₂)_(q)CO—NG¹G², (CH₂)_(q)OG³,—(CH₂)_(q)SO₃G³—(CH₂)_(q)—SO₂-(C₁-C₆)alkyl, —(CH₂)_(q)—SO₂NG¹G², or aheterocycle selected from the group consisting of —(CH₂)_(q)-pyridyl,—(CH₂)_(q)-pyrimidyl, —(CH₂)_(q)-pyraziqyl, —(CH₂)_(q)-isoxazolyl,(CH₂)_(q) oxazolyl, —(CH₂)_(q)-thiazolyl,—(CH₂)_(q)-(1,2,4-oxadiazolyl), —(CH₂)_(q)-imidazolyl,—(CH₂)_(q)-triazolyl and —(CH₂)_(q)-tetrazolyl;

[0161] wherein one of the ring nitrogen atoms of said—(CH₂)_(q)-imidazolyl, —(CH₂)_(q)-triazolyl and —(CH₂)_(q)-tetrazolylmay optionally be substituted by (C₁-C₈)alkyl optionally independentlysubstituted with one or more halo atoms;

[0162] wherein each of said heterocycles may optionally be substitutedon one or more of the ring carbon atoms by one or more substituentsindependently selected from the group consisting of (C₁-C₈)alkyloptionally independently substituted with one or more halo atoms, nitro,cyano, —(CH₂)_(q)—NG¹G², —(CH₂)_(q)—CO₂G³, (CH₂)_(q)—CO-NG¹G²,—(CH₂)_(q)—OG³, (CH₂)_(q)SO₃G³, —(CH₂)_(q)—SO₂—(C₁-C₆)alkyl and—(CH₂)_(q)—SO₂NG¹G²;

[0163] wherein the phenyl moiety of said —(CH₂)_(q)-phenyl mayoptionally be substituted with one or more substituents independentlyselected from the group consisting of (C₁-C₆)alkyl optionallyindependently substituted with one or more halo atoms, hydroxy,(C₁-C₆)alkoxy optionally independently substituted with one or more haloatoms, (C₁-C₆)alkylthio, fluoro, chloro, bromo, iodo, cyano, nitro,—(CH₂)_(q)—NG¹G², —(CH₂)_(q)—CO₂G³, —(CH₂)_(q)—CO-NG¹G², —(CH₂)_(q)—OG³,(CH₂)_(q)SO₃G³, —(CH₂)_(q)SO₂(C₁-C₆)alkyl, —(CH₂)_(q)—SO₂NG¹G²;—(CH₂)_(q)—NG³_SO₂—G³ and —(CH₂)_(q)—NG³_SO₂—NG¹G²; Q⁴ is (CH₂)_(q)—CN,—(CH₂)_(q)CO₂G³, (CH₂)_(q)—SO₃G³, —(CH₂)_(q)—SO₂—(C₁-C₆)alkyl,—(CH₂)_(q)SO₂NG¹G², (CH₂)_(q)CH₂OH, (CH₂)_(q)CHO, (CH₂)_(q)CO-G³,(CH₂)_(q)CONG¹G², or a heterocycle selected from —(CH₂)_(q)-thiazolyl,—(CH₂)_(q)-oxazolyl, —(CH₂)_(q)-imidazolyl, —(CH₂)_(q)-triazolyl,—(CH₂)_(q)-1,2,4-oxadiazolyl, —(CH₂)_(q)-isoxazolyl,—(CH₂)_(q)-tetrazolyl and —(CH₂)_(q)-pyrazolyl;

[0164] wherein one of the ring nitrogen atoms of said—(CH₂)_(q)-imidazolyl, —(CH₂)_(q)-triazolyl and —(CH₂)_(q)-tetrazolylmay optionally be substituted by (C₁-C₆)alkyl optionally independentlysubstituted with one or more halo atoms;

[0165] wherein each of said heterocycles may optionally be substitutedon-one or more of the ring carbon atoms by one or more substituentsindependently selected from the group consisting of hydrogen,(C₁-C₆)alkyl optionally independently substituted with one or more haloatoms, —(CH₂)_(q)—CO-NG¹G², —(CH₂)_(q)—CO₂G³, halo, nitro, cyano,—(CH₂)_(q)—CO-NG¹G², —(CH₂)_(q)—OG³, —(CH₂)_(q)—SO₃G³,(CH₂)_(q)SO₂(C₁-C₆)alkyl, or —(CH₂)_(q)—SO₂NG¹G²;

[0166] Q⁵ is hydrogen or (C₁-C₆)alkyl optionally independentlysubstituted with one or more halo atoms;

[0167] Q⁶ is a covalent bond, oxygen or sulfur;

[0168] Q⁷ is hydrogen or (C₁-C₆)alkyl optionally independentlysubstituted with one or more halo atoms;

[0169] Q⁸ and Q⁹ are independently a covalent bond, oxygen, sulfur, NHor N-(C₁-C₆)alkyl;

[0170] Q¹⁰ is nitro, amino, (C₂-C₉)heteroaryl, (C₂-C₉)heterocycloalkyl,(CH₂)_(p)OR¹¹, (CH₂)_(q)CO₂H, (CH₂)_(q)COR¹³, (CH₂)_(q)SO₂NR¹¹R¹²,(CH₂)_(q)NR¹¹SO₂R¹⁰, (CH₂)_(q)P(O)(OR⁸)(OR⁹), (CH₂)_(q)O(CH₂)_(p)CO₂H,(CH₂)_(q)O(CH₂)_(p)COR¹³, (CH₂)_(q)—(CH₂)_(p)P(O)(OR⁸)(OR⁹),(CH₂)_(q)—O—(CH₂)_(p)SO₂NR¹¹R¹², or (CH₂)_(q)—O—(CH₂)_(p)—NR¹¹SO₂R¹⁰;

[0171] R⁸ and R⁹ are each independently hydrogen or (C₁-C₆)alkyl; and

[0172] wherein G¹ and G² for each occurrence are each independentlyhydrogen, (C₁-C₆)alkyl optionally independently substituted with one ormore halo, (C₁-C₈)alkoxy(C₁-C₆)alkyl or (C₃-C₈)cycloalkyl, or G¹ and G²together with the nitrogen to which they are attached form a saturatedheterocyclic ring having from 3 to 7 carbon atoms wherein one of saidcarbon atoms may optionally be replaced by oxygen, nitrogen or sulfur;

[0173] G³ for each occurrence is independently hydrogen or (C₁-C₆)alkyl;

[0174] R¹⁰ for each occurrence is independently (C₁-C₆)alkyl or(C₁-C₆)alkoxy(C₁-C₆)alkyl;

[0175] R¹¹ and R¹² are taken separately and, for each occurrence, areindependently hydrogen, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, or(C₁-C₆)alkoxy(C₁-C₆)alkyl, or

[0176] R¹¹ and R¹² are taken together with the nitrogen atom to whichthey are attached and form a pyrrolidine, piperidine or morpholine ringwherein said pyrrolidine, piperidine or morpholine may optionally besubstituted at any carbon atom by (C₁-C₄)alkyl or (C₁-C₄)alkoxy;

[0177] R¹³ for each occurrence is independently hydrogen, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, NR¹R¹², (C₃-C₈)cycloalkyl, or (C₁-C₆)alkoxy(C₁-C₆)alkylwherein R¹¹ and R¹² are as defined above;

[0178] R¹⁴ and R¹⁵ are each independently hydrogen, halo, (C₁-C₆)alkyl,nitro, cyano, trifluoromethyl, SO₂R¹⁰, SO₂NR¹¹R¹², NR¹¹R¹², COR¹³,CO₂R¹¹, (C₁-C₆)alkoxy, NR¹¹SO₂R¹⁰, NR¹¹COR¹³, NR¹¹CO₂R¹¹ or OR¹¹;

[0179] p for each occurrence is independently an integer of 1 to 6; and

[0180] q for each occurrence is independently 0 or an integer of 1 to 6;

[0181] with the proviso that when Q⁹ is O or S then n is not 0;

[0182] with the proviso that when Q¹ is oxygen or sulfur then Q³ isabsent; and

[0183] with the proviso that when Q² is nitrogen then Q⁵ is absent;

[0184] comprising reacting a compound of the formula

[0185] wherein R¹ is halo and wherein n, R², R³ and Y are as definedabove, with ammonium formate in the presence of palladium-on-carbon.

[0186] The present invention further relates to a process wherein acompound of the formula

[0187] is formed by reacting a compound of the formula

[0188] wherein R¹ is hydrogen or halo, and wherein n, R² and Y are asdefined above, with an organic acid anhydride, a dicarbonate or anorganic acid chloride.

[0189] The present invention further relates to a process wherein thedicarbonate is di-tert-butyl dicarbonate

[0190] The present invention further relates to a process wherein thecompound of the formula

[0191] is formed by reacting the compound

[0192] wherein n, R¹, R² and X are as defined above, with an amine ofthe formula H₂NY, wherein Y is as defined above, in the presence ofN,N-diisopropylethylamine.

[0193] This invention relates to a process for preparing a compound ofthe formula

[0194] wherein n is 0, 1, 2 or 3;

[0195] each R² is independently hydrogen, halo, trifluoromethyl, cyano,SR⁴, OR⁴, SO₂R⁴, OCOR⁵, or (C₀-C₁₀)alkyl wherein the alkyl group isoptionally substituted by hydroxy, halo, cyano, N(R⁴)₂, SR⁴,trifluoromethyl, OR⁴, (C₃-C₈)cycloalkyl, (C₆-C₁₀)aryl, NR⁴COR⁵, COR⁵,SO₂R⁵, OCOR⁵, NR⁴SO₂R⁵ and NR⁴CO₂ R⁴;

[0196] R⁴ and R⁵, for each occurrence, are each independently selectedfrom hydrogen, (C₁-C₁₀)alkyl, (C₁-C₁₀)alkoxy,(C₃-C₈)cycloalkyl,(C₆-C₁₀)aryl, (C₂-C₉)heterocycloalkyl,(C₂-C₉)heteroaryl or (C₁-C₆)aryl wherein the alkyl group is optionallysubstituted by the group consisting of hydroxy, halo, carboxy,(C₁-C₁₀)alkyl-CO₂, (C₁-C₁₀)alkylsulfonyl, (C₃-C₈)cycloalkyl,(C₁-C₁₀)alkoxy, or (C₁-C₆)alkyl; and wherein the aryl, heterocycloalkyland heteroaryl groups are optionally substituted by one to four groupsconsisting of halo, nitro, oxo, ((C₁-C₆)alkyl)₂amino, pyrrolidine,piperidine, (C₁-C₁₀)alkyl, (C₁-C₁₀)alkoxy, (C₁-C₁₀)alkylthio and(C₁-C₁₀)alkyl wherein the alkyl group is optionally substituted by oneto four groups selected from hydroxy, halo, carboxy, (C₁-C₆)alkyl-CO₂,(C₁-C₆)alkylsulfonyl, (C₃-C₈)cycloalkyl and (C₁-C₆)alkoxy;

[0197] or R⁵ is N(R⁴)₂ wherein R⁴ is as defined above;

[0198] R⁶ is COR⁷ or CO₂R⁷ wherein R⁷ is (C₁-C₈)alkyl; and

[0199] Y is

[0200] wherein:

[0201] Q¹ is oxygen, nitrogen or sulfur;

[0202] Q² is carbon or nitrogen;

[0203] Q³ is hydrogen, —(CH₂)_(q)-phenyl, —(C₁-C₁₀)alkyl,—(CH₂)_(q)—NG¹G², —(CH₂)_(q)—CO₂G³, (CH₂)_(q)CO—NG¹G², (CH₂)_(q)OG³,(CH₂)_(q)SO₃G³, (CH₂)_(q)SO₂(C₁-C₆)alkyl, —(CH₂)_(q)—SO₂NG¹G², or aheterocycle selected from the group consisting of —(CH₂)_(q)-pyridyl,—(CH₂)_(q)-pyrimidyl, —(CH₂)_(q)-pyraziqyl, —(CH₂)_(q)-isoxazolyl,(CH₂)_(q) oxazolyl, —(CH₂)_(q)-thiazolyl,—(CH₂)_(q)-(1,2,4-oxadiazolyl), —(CH₂)_(q)-imidazolyl,—(CH₂)_(q)-triazolyl and —(CH₂)_(q)-tetrazolyl;

[0204] wherein one of the ring nitrogen atoms of said—(CH₂)_(q)-imidazolyl, —(CH₂)_(q)-triazolyl and —(CH₂)_(q)-tetrazolylmay optionally be substituted by (C₁-C₈)alkyl optionally independentlysubstituted with one or more halo atoms;

[0205] wherein each of said heterocycles may optionally be substitutedon one or more of the ring carbon atoms by one or more substituentsindependently selected from the group consisting of (C₁-C₈)alkyloptionally independently substituted with one or more halo atoms, nitro,cyano, —(CH₂)_(q)—NG¹G², —(CH₂)_(q)—CO₂G³, —(CH₂)_(q)—CO-NG¹G²,(CH₂)_(q)OG³, —(CH₂)_(q)—SO₃G³, —(CH₂)_(q)—SO₂-(C₁-C₆)alkyl and—(CH₂)_(q)—SO₂NG¹G²;

[0206] wherein the phenyl moiety of said —(CH₂)_(q)-phenyl mayoptionally be substituted with one or more substituents independentlyselected from the group consisting of (C₁-C₆)alkyl optionallyindependently substituted with one or more halo atoms, hydroxy,(C₁-C₆)alkoxy optionally independently substituted with one or more haloatoms, (C₁-C₆)alkylthio, fluoro, chloro, bromo, iodo, cyano, nitro,—(CH₂)_(q)—NG¹G², —(CH₂)_(q)—CO₂G³, —(CH₂)_(q)—CO-NG¹G², —(CH₂)_(q)—OG³,(CH₂)_(q)SO₃G³—(CH₂)_(q)—SO₂(C₁-C₆)alkyl, —(CH₂)_(q)—SO₂NG¹G²;—(CH₂)_(q)—NG³—SO₂-G³ and —(CH₂)_(q)—NG³—SO₂—NG¹G²; Q⁴ is —(CH₂)_(q)—CN,—(CH₂)_(q)CO₂G³, —(CH₂)_(q)SO₃G³, —(CH₂)_(q)—SO₂—(C₁-C₆)alkyl,(CH₂)_(q)SO₂NG¹G², (CH₂)_(q)CH₂OH, (CH₂)_(q)CHO, (CH₂)_(q)CO-G³,(CH₂)_(q)CONG¹G², or a heterocycle selected from —(CH₂)_(q)-thiazolyl,—(CH₂)_(q)-oxazolyl, —(CH₂)_(q)-imidazolyl, —(CH₂)_(q)-triazolyl,—(CH₂)_(q)-1,2,4-oxadiazolyl, —(CH₂)_(q)-isoxazolyl,—(CH₂)_(q)-tetrazolyl and —(CH₂)_(q)-pyrazolyl;

[0207] wherein one of the ring nitrogen atoms of said—(CH₂)_(q)-imidazolyl, —(CH₂)_(q)-triazolyl and —(CH₂)_(q)-tetrazolylmay optionally be substituted by (C₁-C₆)alkyl optionally independentlysubstituted with one or more halo atoms;

[0208] wherein each of said heterocycles may optionally be substitutedon one or more of the ring carbon atoms by one or more substituentsindependently selected from the group consisting of hydrogen,(C₁-C₆)alkyl optionally independently substituted with one or more haloatoms, —(CH₂)_(q)—CO-NG¹G² (CH₂)_(q)CO₂G³, halo, nitro, cyano,—(CH₂)_(q)—CO-NG¹G², —(CH₂)_(q)—OG³, —(CH₂)_(q)—SO₃G³,—(CH₂)_(q)—SO₂—(C₁-C₆)alkyl, or —(CH₂)_(q)—SO₂NG¹G²;

[0209] Q⁵ is hydrogen or (C₁-C₆)alkyl optionally independentlysubstituted with one or more halo atoms;

[0210] Q⁶ is a covalent bond, oxygen or sulfur;

[0211] Q⁷ is hydrogen or (C₁-C₆)alkyl optionally independentlysubstituted with one or more halo atoms;

[0212] Q⁸ and Q⁹ are independently a covalent bond, oxygen, sulfur, NHor N-(C₁-C₆)alkyl;

[0213] Q¹⁰ is (CH₂)_(p)OR¹¹, (CH₂)_(q)CO₂H, (CH₂)_(q)COR¹³,(CH₂)_(q)SO₂NR¹¹R¹², (CH₂)_(q)—NR¹¹SO₂R¹⁰, (CH₂)_(q)P(O)(OR⁸)(OR⁹),(CH₂)_(q)O(CH₂)_(p)CO₂H, (CH₂)_(q)O(CH₂)_(p)COR¹³,(CH₂)_(q)—O—(CH₂)_(p)P(O)(OR⁸)(OR⁹), (CH₂)_(q)—O—(CH₂)_(p)SO₂NR¹¹R¹², or(CH₂)_(q)—O—(CH₂)_(p)—NR¹¹SO₂R¹⁰;

[0214] R⁸ and R⁹ are each independently hydrogen or (C₁-C₆)alkyl; and

[0215] wherein G¹ and G² for each occurrence are each independentlyhydrogen, (C₁-C₆)alkyl optionally independently substituted with one ormore halo, (C₁-C₈)alkoxy(C₁-C₆)alkyl or (C₃-C₈)cycloalkyl, or G¹ and G²together with the nitrogen to which they are attached form a saturatedheterocyclic ring having from 3 to 7 carbon atoms wherein one of saidcarbon atoms may optionally be replaced by oxygen, nitrogen or sulfur;

[0216] G³ for each occurrence is independently hydrogen or (C₁-C₆)alkyl;

[0217] R¹⁰ for each occurrence is independently (C₁-C₆)alkyl or(C₁-C₆)alkoxy(C₁-C₆)alkyl;

[0218] R¹¹ and R¹² are taken separately and, for each occurrence, areindependently hydrogen, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, or(C₁-C₆)alkoxy(C₁-C₆)alkyl, or

[0219] R¹¹ and R¹² are taken together with the nitrogen atom to whichthey are attached and form a pyrrolidine, piperidine or morpholine ringwherein said pyrrolidine, piperidine or morpholine may optionally besubstituted at any carbon atom by (C₁-C₄)alkyl or (C₁-C₄)alkoxy;

[0220] R¹³ for each occurrence is independently hydrogen, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, NR¹R¹², (C₃-C₈)cycloalkyl, or (C₁-C₆)alkoxy(C₁-C₆)alkylwherein R¹¹ and R¹² are as defined above;

[0221] R¹⁴ and R¹⁵ are each independently hydrogen, halo, (C₁-C₆)alkyl,nitro, cyano, trifluoromethyl, SO₂R¹⁰, SO₂NR¹¹R², NR¹¹R¹², COR¹³,CO₂R¹¹, (C₁-C₆)alkoxy, NR¹¹SO₂R¹⁰, NR¹¹COR¹³, NR¹¹CO₂R¹¹ or OR¹¹;

[0222] p for each occurrence is independently an integer of 1 to 6; and

[0223] q for each occurrence is independently 0 or an integer of 1 to 6;

[0224] with the proviso that when Q⁹ is O or S then n is not 0;

[0225] with the proviso that when Q¹ is oxygen or sulfur then Q³ isabsent; and

[0226] with the proviso that when Q² is nitrogen then Q⁵ is absent;

[0227] comprising (a) reacting the compound of the formula

[0228] wherein R¹ is hydrogen or halo, and n, R¹, R², R³ and X are asdefined above, with an amine of the formula H₂NY, wherein Y is asdefined above, in the presence of N,N-diisopropylethylamine;

[0229] (b) reacting the compound of the formula VII so formed

[0230] wherein R¹ is hydrogen or halo and wherein n, R² and Y are asdefined above with an organic acid anhydride, a dicarbonate or anorganic acid chloride to form a compound of the formula

[0231] wherein n, R¹, R², R⁶ and Y are as defined above and

[0232] (c) reacting the compound of formula VI, wherein R¹ is halo, soformed with ammonium formate in the presence of palladium-on-carbon.

[0233] This invention relates to a process for preparing a compound ofthe formula

[0234] wherein n is 0, 1, 2 or 3;

[0235] R¹ is hydrogen or halo;

[0236] each R² is independently hydrogen, halo, trifluoromethyl, cyano,SR⁴, OR⁴, SO₂R⁴, OCOR⁵, or (C₁-C₁₀)alkyl wherein the alkyl group isoptionally substituted by hydroxy, halo, cyano, N(R⁴)₂, SR⁴,trifluoromethyl, OR⁴, (C₃-C₈)cycloalkyl, (C₆-C₁₀)aryl, NR⁴COR⁵, COR⁵,SO₂R⁵, OCOR⁵, NR⁴SO₂R⁵ and NR⁴CO₂ R⁴;

[0237] R⁴ and R⁵, for each occurrence, are each independently selectedfrom hydrogen, (C₁-C₁₀)alkyl, (C₁-C₁₀)alkoxy,(C₃-C₈)cycloalkyl,(C₆-C₁₀)aryl, (C₂-C₉)heterocycloalkyl,(C₂-C₉)heteroaryl or (C₁-C₆)aryl wherein the alkyl group is optionallysubstituted by the group consisting of hydroxy, halo, carboxy,(C₁-C₁₀)alkyl-CO₂, (C₁-C₁₀)alkylsulfonyl, (C₃-C₈)cycloalkyl,(C₁-C₁₀)alkoxy, and or (C₁-C₆)alkyl; and wherein the aryl,heterocycloalkyl and heteroaryl groups are optionally substituted by oneto four groups consisting of halo, nitro, oxo, ((C₁-C₆)alkyl)₂amino,pyrrolidine, piperidine, (C₁-C₁₀)alkyl, (C₁-C₁₀)alkoxy,(C₁-C₁₀)alkylthio and (C₁-C₁₀)alkyl wherein the alkyl group isoptionally substituted by one to four groups selected from hydroxy,halo, carboxy, (C₁-C₆)alkyl-CO₂, (C₁-C₆)alkylsulfonyl, (C₃-C₈)cycloalkyland (C₁-C₆)alkoxy;

[0238] or R⁵ is N(R⁴)₂ wherein R⁴ is as defined above;

[0239] comprising reacting a compound of the formula

[0240] wherein n, R¹, R² and X are as defined above, with anon-nucleophilic base.

[0241] The present invention further relates to a process wherein thenon-nucleophilic base is sodium hydroxide, potassium hydroxide, sodiumhydride, potassium tert-butoxide or 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0242] This invention relates to a compound of the formula

[0243] wherein n is 0, 1, 2 or 3;

[0244] R¹ is hydrogen or halo;

[0245] each R² is independently hydrogen, halo, trifluoromethyl, cyano,SR⁴, OR⁴, SO₂R⁴, OCOR⁵, or (C₁-C₁₀)alkyl wherein the alkyl group isoptionally substituted by hydroxy, halo, cyano, N(R⁴)₂, SR⁴,trifluoromethyl, OR⁴, (C₃-C₈)cycloalkyl, (C₆-C₁₀)aryl, NR⁴COR⁵, COR⁵,SO₂R⁵, OCOR⁵, NR⁴SO₂R⁵ and NR⁴CO₂ R⁴;

[0246] R⁴ and R⁵, for each occurrence, are each independently selectedfrom hydrogen, (C₁-C₁₀)alkyl, (C₁-C₁₀)alkoxy,(C₃-C₈)cycloalkyl,(C₆-C₁₀)aryl, (C₂-C₉)heterocycloalkyl,(C₂-C₉)heteroaryl or (C₁-C₆)aryl wherein the alkyl group is optionallysubstituted by the group consisting of hydroxy, halo, carboxy,(C₁-C₁₀)alkyl-CO₂, (C₁-C₁₀)alkylsulfonyl, (C₃-C₈)cycloalkyl,(C₁-C₁₀)alkoxy, or (C₁-C₆)alkyl; and wherein the aryl, heterocycloalkyland heteroaryl groups are optionally substituted by one to four groupsconsisting of halo, nitro, oxo, ((C₁-C₆)alkyl)₂amino, pyrrolidine,piperidine, (C₁-C₁₀)alkyl, (C₁-C₁₀)alkoxy, (C₁-C₁₀)alkylthio and(C₁-C₁₀)alkyl wherein the alkyl group is optionally substituted by oneto four groups selected from hydroxy, halo, carboxy, (C₁-C₆)alkyl-CO₂,(C₁-C₆)alkylsulfonyl, (C₃-C₈)cycloalkyl and (C₁-C₆)alkoxy;

[0247] or R⁵ is N(R⁴)₂ wherein R⁴ is as defined above.

[0248] The present invention further relates to a compound wherein thecompound of formula XI is the R enantiomer

[0249] wherein R¹ is chloro and R² is hydrogen.

[0250] The present invention further relates to a compound wherein thecompound of formula XI is the R enantiomer

[0251] wherein R¹ and R² are hydrogen.

[0252] This invention relates to a compound of the formula

[0253] wherein n is 0, 1, 2 or 3;

[0254] R¹ is hydrogen or halo;

[0255] each R² is independently hydrogen, halo, trifluoromethyl, cyano,SR⁴, OR⁴, SO₂R⁴, OCOR⁵, or (C₁-C₁₀)alkyl wherein the alkyl group isoptionally substituted by hydroxy, halo, cyano, N(R⁴)₂, SR⁴,trifluoromethyl, OR⁴, (C₃-C₈)cycloalkyl, (C₆-C₁₀)aryl, NR⁴COR⁵, COR⁵,SO₂R⁵, OCOR⁵, NR⁴SO₂R⁵ and NR⁴CO₂ R⁴;

[0256] R⁴ and R⁵, for each occurrence, are each independently selectedfrom hydrogen, (C₁-C₁₀)alkyl, (C₁-C₁₀)alkoxy,(C₃-C₈)cycloalkyl,(C₆-C₁₀)aryl, (C₂-C₉)heterocycloalkyl,(C₂-C₉)heteroaryl or (C₁-C₆)aryl wherein the alkyl group is optionallysubstituted by the group consisting of hydroxy, halo, carboxy,(C₁-C₁₀)alkyl-CO₂, (C₁-C₁₀)alkylsulfonyl, (C₃-C₈)cycloalkyl,(C₁-C₁₀)alkoxy, or (C₁-C₆)alkyl; and wherein the aryl, heterocycloalkyland heteroaryl groups are optionally substituted by one to four groupsconsisting of halo, nitro, oxo, ((C₁-C₆)alkyl)₂amino, pyrrolidine,piperidine, (C₁-C₁₀)alkyl, (C₁-C₁₀)alkoxy, (C₁-C₁₀)alkylthio and(C₁-C₁₀)alkyl wherein the alkyl group is optionally substituted by oneto four groups selected from hydroxy, halo, carboxy, (C₁-C₆)alkyl-CO₂,(C₁-C₆)alkylsulfonyl, (C₃-C₈)cycloalkyl and (C₁-C₆)alkoxy; or R⁵ isN(R⁴)₂ wherein R⁴ is as defined above.

[0257] The present invention further relates to a compound wherein thecompound of formula XI is the R enantiomer

[0258] wherein R¹ is chloro and R² is hydrogen.

[0259] The present invention further relates to a compound wherein thecompound of formula XI is the R enantiomer

[0260] wherein R¹ and R² are hydrogen.

[0261] This invention relates to a compound of the formula

[0262] wherein n is 0, 1, 2 or 3;

[0263] R¹ is hydrogen or halo;

[0264] each R² is independently hydrogen, halo, trifluoromethyl, cyano,SR⁴, OR⁴, SO₂R⁴, OCOR⁵, or (C₁-C₁₀)alkyl wherein the alkyl group isoptionally substituted by hydroxy, halo, cyano, N(R⁴)₂, SR⁴,trifluoromethyl, OR⁴, (C₃-C₈)cycloalkyl, (C₆-C₁₀)aryl, NR⁴COR⁵, COR⁵,SO₂R⁵, OCOR⁵, NR⁴SO₂R⁵ and NR⁴CO₂ R⁴;

[0265] R³ is tetrahydrofuranyl, tetrahydropyranyl or a silyl protetctinggroup;

[0266] X is halo, methanesulfonyloxy, benzenesulfonyloxy,p-toluenesulfonyloxy, m-nitrobenzenesulfonyloxy orp-nitrobenzenexulfonyloxy;

[0267] R⁴ and R⁵, for each occurrence, are each independently selectedfrom hydrogen, (C₁-C₁₀)alkyl,(C₁-C₁₀)alkoxy,(C₃-C₈)cycloalkyl,(C₆-C₁₀)aryl, (C₂-C₉)heterocycloalkyl,(C₂-C₉)heteroaryl or (C₁-C₆)aryl wherein the alkyl group is optionallysubstituted by the group consisting of hydroxy, halo, carboxy,(C₁-C₁₀)alkyl-CO₂, (C₁-C₁₀)alkylsulfonyl, (C₃-C₈)cycloalkyl,(C₁-C₁₀)alkoxy, or (C₁-C₆)alkyl; and wherein the aryl, heterocycloalkyland heteroaryl groups are optionally substituted by one to four groupsconsisting of halo, nitro, oxo, ((C₁-C₆)alkyl)₂amino, pyrrolidine,piperidine, (C₁-C₁₀)alkyl, (C₁-C₁₀)alkoxy, (C₁-C₁₀)alkylthio and(C₁-C₁₀)alkyl wherein the alkyl group is optionally substituted by oneto four groups selected from hydroxy, halo, carboxy, (C₁-C₆)alkyl-CO₂,(C₁-C₆)alkylsulfonyl, (C₃-C₈)cycloalkyl and (C₁-C₆)alkoxy;

[0268] or R⁵ is N(R⁴)₂ wherein R⁴ is as defined above.

[0269] The present invention further relates to a compound wherein thecompound of formula IX is the R enantiomer

[0270] wherein R¹ is chloro; R² is hydrogen; R³ istert-butyldimethylsilyl; and X is p-toluenesulfonyloxy.

[0271] The present invention further relates to a compound wherein thecompound of formula IX is the R enantiomer

[0272] wherein R¹ and R² are hydrogen.

[0273] This invention relates to a compound of the formula

[0274] wherein n is 0, 1, 2 or 3;

[0275] m is 1 or 2;

[0276] R¹ is hydrogen or halo;

[0277] each R² is independently hydrogen, nitro, halo, trifluoromethyl,cyano, SR⁴, OR⁴, SO₂R⁴, OCOR⁵, or (C₁-C₁₀)alkyl wherein the alkyl groupis optionally substituted by hydroxy, halo, cyano, N(R⁴)₂, SR⁴,trifluoromethyl, OR⁴, (C₃-C₈)cycloalkyl, (C₆-C₁₀)aryl, NR⁴COR⁵, COR⁵,SO₂R⁵, OCOR⁵, NR⁴SO₂R⁵ and NR⁴CO₂ R⁴;

[0278] R⁴ and R⁵, for each occurrence, are each independently selectedfrom hydrogen, (C₁-C₁₀)alkyl, (C₁-C₁₀)alkoxy,(C₃-C₈)cycloalkyl,(C₆-C₁₀)aryl, (C₂-C₉)heterocycloalkyl,(C₂-C₉)heteroaryl or (C₁-C₆)aryl wherein the alkyl group is optionallysubstituted by the group consisting of hydroxy, halo, carboxy,(C₁-C₁₀)alkyl-CO₂, (C₁-C₁₀)alkylsulfonyl, (C₃-C₈)cycloalkyl,(C₁-C₁₀)alkoxy, or (C₁-C₆)alkyl; and wherein the aryl, heterocycloalkyland heteroaryl groups are optionally substituted by one to four groupsconsisting of halo, nitro, oxo, ((C₁-C₆)alkyl)₂amino, pyrrolidine,piperidine, (C₁-C₁₀)alkyl, (C₁-C₁₀)alkoxy, (C₁-C₁₀)alkylthio and(C₁-C₁₀)alkyl wherein the alkyl group is optionally substituted by oneto four groups selected from hydroxy, halo, carboxy, (C₁-C₆)alkyl-CO₂,(C₁-C₆)alkylsulfonyl, (C₃-C₈)cycloalkyl and (C₁-C₆)alkoxy;

[0279] or R⁵ is N(R⁴)₂ wherein R⁴ is as defined above.

[0280] The present invention further relates to a compound wherein m is2, R¹ is chloro, and R² is hydrogen.

[0281] The present invention further relates to a compound wherein m is2 and R² and R³ are hydrogen.

[0282] The present invention further relates to a compound wherein thecompound of formula XVII is the R enantiomer

[0283] wherein m is 2 and R¹ and R² are hydrogen.

[0284] The present invention further relates to a compound wherein thecompound of formula XVII is the R enantiomer

[0285] wherein m is 2, R¹ is chloro and R² are hydrogen.

[0286] This invention relates to a compound of the formula

[0287] wherein R¹ is hydrogen or chloro and BOC is tert-butoxycarbonyl.

[0288] This invention relates to a compound of the formula

[0289] wherein R¹ is hydrogen or chloro and BOC is tert-butoxycarbonyl.

[0290] This invention relates to a compound of the formula

[0291] wherein BOC is tert-butoxycarbonyl.

[0292] This invention relates to a compound of the formula

[0293] wherein R¹ is hydrogen or chloro.

DETAILED DESCRIPTION OF THE INVENTION

[0294] The following reaction Scheme illustrates the preparation of thecompounds of the present invention. Unless otherwise indicated n, R¹,R², R³, R⁶, X and Y in the reaction Schemes and the discussion thatfollow are defined as above.

[0295] In reaction 1 of Preparation A, the 5-cyanopyridine compound offormula XIV is converted to the corresponding 5-formylpyridine compoundof formula XIII by reacting XIV with a reducing agent, such asdiisobutylaluminum hydride, in the presence of an aprotic solvent, suchas toluene. The reaction is stirred at a temperature range between about0° C. to about 10° C., preferably about 5° C., for a time period betweenabout 15 minutes to about 45 minutes, preferably about 30 minutes. Theresultant intermediate is then hydrolized with an acid or base,preferably methanol and sulfuric acid. The reaction mixture so formed iswarmed to room temperature and stirred for an additional time periodbetween about 30 minutes to about 90 minutes, preferably about 1 hour.

[0296] In reaction 2 of Preparation A, the 5-formylpyridine compound offormula XIII is converted to the corresponding 5-vinylpyridine compoundof formula XII by reacting XIII with a methylating reagent, preferablyprepared from methyltriphenylphosphonium bromide and potassiumtert-butoxide, in the presence of a polar aprotic solvent, such astetrahydrofuran. The resulting reaction mixture is stirred for a timeperiod between about 15 minutes to about 45 minutes, preferably about 30minutes, at a temperature range between about −40° C. to about 50° C.,preferably about 5° C.

[0297] In reaction 3 of Preparation A, the 5-vinylpyridine compound offormula XII is converted to the corresponding diol compound of formulaXI by reacting XII with a dihydroxylating agent, such as osmiumtetroxide or potassium permanganate, preferably osmium tetroxide, withor without a co-oxidant, such as potassium ferricyanide, hydrogenperoxide, t-butyl hydroperoxide or N-methylmorpholine-N-oxide,preferably potassium ferricyanide, in the presence of tert-butanol andwater. Such oxidations can be performed in the presence of acoordinating ligand, such as hydroquinidine 1,4-phthalazinediyl dietheror hydroquinine 1,4-phthalazinediyl diether, which affords theenantiomerically enriched diol. The reaction mixture is stirred at atemperature range between about −30° C. to about 10° C., preferablyabout 5° C., for a time period between about 4 hours to about 18 hours,preferably about 6 hours.

[0298] In reaction 4 of Preparation A, the diol compound of formula XIis converted to the corresponding compound of formula X by reacting XIwith the appropriate sulfonylchloride, such as p-toluenesulfonylchloride, methanesulfonyl chloride, m-nitrobenzenesulfonyl chloride,p-nitrobenzenesulfonyl chloride or benzenesulfonyl chloride, preferablyp-toluenesulfonyl chloride, in the presence of a base. Suitable baseswhich may be used include lower trialkylamines, pyridine, and pyridinederivatives. Preferred bases include, but are not limited to,triethylamine, diisopropylethylamine, pyridine, 2,4,6-collidine and2,6-lutidine. Pyridine is the most preferred base. It is preferred thatthe solvent is a polar solvent such as (a) an ether derivative,including but not limited to, tetrahydrofuran, dioxane anddimethoxyethane; (b) chlorinated hydrocarbons, including but not limitedto, carbon tetrachloride, chloroform and methylene chloride; (c)aromatic hydrocarbons including but not limited to benzene, toluene andxylene; (d) dimethylformamide; (e) N-methyl-2-pyrrolidinone; (f)dimethylacetamide; or (g) pyridine or any mixture of these solvents.Generally the most preferred solvent is pyridine. The reaction mixtureis stirred at a temperature range between about 0° C. to about 10° C.,preferably about 5° C., for a time period between about 6 hours to about24 hours, preferably about 12 hours. To prepare compounds of formula X,wherein X is halo, the compound of formula XI, wherein X is tosylate, isreacted with a halogenating agent in a reaction inert solvent. Thereaction is carried out at a temperature between 25° C. to the refluxtemperature of the solvent utilized, preferably the reflux temperatureof the solvent. Halogenating agents are compounds which are capable oftransferring an organic substrate having a leaving group, i.e. sylate,which can be displaced by the halide ion. Preferred halogenating agentsare lithium halides, such as lithium chlorides and the preferred solventis a polar protic solvent, such as ethanol.

[0299] In reaction 5 of Preparation A, the compound of formula X isconverted to the corresponding compound of formula IX by reacting X witha silyating agent, which include but are not limited totrialkylchlorosilanes, such as tert-butyldimethylsilyl chloride,triethylchlorosilane and triisopropylchlorosilane oralkylarylchlorosilanes, such as diphenylmethylchlorosilane, in thepresence of a base and a polar protic solvent. A preferred silyatingagent is tert-butyldimethylsilyl chloride. Suitable bases include, butare not limited to, triethylamine, N,N-diisopropylethylamine, imidazole,pyridine, 2,6-lutidine and N-methylmorpholine, preferably imidazole.Suitable polar protic solvents include, but are not limited to,dimethylacetamide, tetrahydrofuran, dimethylformamide, methylenechloride and chloroform, preferably dimethylformamide. The reaction iscarried out at a temperature between about 0° C. to about 10° C.,preferably about 5° C., and then warmed to room temperature over a timeperiod between 14 hours to about 22 hours, preferably about 18 hours.

[0300] In reaction 1 of Scheme 1, the compound of formula V is convertedto the corresponding compound of formula IV by reacting V with an amineof the formula, H₂NY, in the presence of N,N-diisopropylethylamine and apolar aprotic solvent, such as dimethyl sulfoxide. The reaction isstirred a temperature between 70° C. to about 90° C., preferably about80° C., for a time period between about 5 hours to about 9 hours,preferably about 7 hours.

[0301] In reaction 2 of Scheme 1, the compound of formula IV isconverted to the corresponding compound of formula III by reacting IV,wherein R⁶ is an amine protecting group, with an organic acid anhydride,a dicarbonate, such as di-tert-butyl dicarbonate or an organic acidchloride. The term “amine protecting group” includes an organic radicalwhich is readily attached to an amine nitrogen atom and which block saidnitrogen atom from reacting with reagents and substrates used in andintermediates and transition state molecules formed in subsequentchemical transformations. The resulting reaction mixture is allowed tostir, at room temperature for a time period between about 2 hours toabout 6 hours, preferably about 4 hours.

[0302] In reaction 3 of Scheme 1, the compound of formula III, whereinR¹ is halo, is converted to the corresponding compound of formula II bytreating III with ammonium formate in the presence ofpalladium-on-carbon and a polar protic solvent, such as methanol. Thereaction is allowed to stir at room temperature for a time periodbetween about 1 hour to about 3 hours, preferably about 2 hours.

[0303] In reaction 4 of Scheme 1, the compound of formula II isconverted to the corresponding compound of formula I by treating 11 withtetra-n-butylammonium fluoride in the presence of an aprotic solvent,such as tetrahydrofuran. The reaction is stirred at room temperature fora time period between about 3 hours to about 12 hours, preferably about8 hours.

[0304] In reaction 1 of Scheme 2, the compound of formula VII isconverted to the corresponding compound of formula VII according to aprocedure analogous to the procedure described above in reaction 1 ofScheme 1.

[0305] In reaction 2 of Scheme 2, the compound of formula VII isconverted to the corresponding compound of formula VI according to aprocedure analogous to the procedure described above in reaction 2 ofScheme 1.

[0306] In reaction 3 of Scheme 2, the compound of formula VI, wherein R¹is halo, is converted to the corresponding compound of formula Iaccording to a procedure analogous to the procedure described above inreaction 3 of Scheme 1.

[0307] In reaction 1 of Scheme 3, the compound of formula X is convertedto the corresponding compound of formula IX by reacting X with anon-nucleophilic base, such as sodium hydroxide, potassium hydroxide,sodium hydride, potassium tert-butoxide or1,8-diazabicyclo[5.4.0]undec-7-ene. The reaction is stirred, in areaction inert solvent, at a temperature between about −20° C. to about100° C. The preferred reaction inert solvent is a polar non-hydroxylicsolvent such as an ether derivative including but not limited totetrahydrofuran, dioxane and dimethoxyethane; chlorinated hydrocarbonsincluding but not limited to carbon tetrachloride, chloroform andmethylene chloride; aromatic hydrocarbons including but not limited tobenzene, toluene and xylene; dimethylformamide; dimethylsulfoxide or anymixture of these solvents. Generally the most preferred solvent istetrahydrofuran.

EXAMPLE 1 2-Chloro-5-formylpyridine

[0308] To a cooled 5° C., stirred solution of 2-chloro-5-cyanopyridine(25.0 grams) in anhydrous toluene (540 mL) was added a 1 M solution ofdiisobutylaluminum hydride (189 mL) over a 30 minute period. Theresulting red-colored solution was treated with methanol (50 mL) and 2Msulfuric acid (150 mL), sequentially. The resulting biphasic solutionwas allowed to warm to ambient temperature and stirred for 1 hour. Thereaction mixture was extracted with ethyl acetate, the combined organiclayers were washed with saturated aqueous sodium bicarbonate andsaturated aqueous brine. The organic phase was stirred over activatedcharcoal for 20 minutes, dried over anhydrous sulfate and concentratedin vacuo to afford the title compound as a light-yellow colored solid,23.5 grams ¹H NMR (400 MHz, CDCl₃) δ=10.08 (s, 1H); 8.85 (s, 1H);8.12(d, 1H); 7.50 (d, 1H).

EXAMPLE 2 2-Chloro-5-vinylpyridine

[0309] To a cooled 5° C., stirred slurry of methyltriphenylphosphoniumbromide (75.7 grams) in tetrahydrofuran (530 mL) was added potassiumt-butoxide (23.8 grams) portionwise over a 5 minute period to produce ayellow slurry. After 30 minutes, 2-chloro-5-formylpyridine (25.0 grams)was added in one portion to produce a purple colored slurry. After anadditional 30 minutes, the reaction mixture was treated with saturatedaqueous ammonium chloride (200 mL) and a majority of the tetrahydrofuranwas removed in vacuo. The resulting mixture was washed with ethylacetate, the combined organic layers washed with saturated aqueousbrine, stirred over activated charcoal for 20 minutes, dried overanhydrous sodium sulfate and concentrated in vacuo. The resultingsemi-solid was stirred for 30 minutes with a solution of 2:1 diethylether/petroleum ether (375 mL), filtered and the solids washed with anadditional portion of 2:1 diethyl ether/petroleum ether (300 mL). Thecombined filtrates were concentrated in vacuo, pre-loaded on 60 grams ofsilica gel and chromatographed over 700 grams of silica gel eluting witha gradient of ethyl acetate(0-8%)/hexanes to afford the title compoundas a colorless oil, 15.2 grams ¹H NMR (400 MHz, CDCl₃): δ=8.35 (s, 1H);7.69(d, 1H); 6.65 (dd, 1H); 5.79 (d, 1H); 5.40 (d, 1H).

EXAMPLE 3 (R)-1-(6-Choro-pyridin-3-yl)-ethane-1,2-diol

[0310] To a cooled 5° C., stirred slurry of AD_Mix-P® (150 g) in water(530 mL) and t-butanol (450 mL) was added a solution of2-chloro-5-vinylpyridine (15.0 grams) in t-butanol (80 mL). After 6hours, solid sodium sulfite (160 grams) was added and the resultingslurry was allowed to stir at ambient temperature for 30 minutes. Thismixture was extracted with ethyl acetate (3 times), the combined organiclayers were washed with saturated aqueous brine, dried over sodiumsulfate and concentrated in vacuo. The resulting oil was chromatographedon 500 grams of silica gel eluting with a gradient of ethyl acetate(70-80%)/hexanes to afford the title compound as a colorless oil, 17.8grams ¹H NMR (400 MHz, CDCl₃): δ=8.35 (s, 1H); 7.71(d, 1H); 7.30(d, 1H);4.85 (dd, 1H); 3.63 (dd, 1H).

EXAMPLE 4 (R)-Toluene-4-sulfonic Acid2-(6-chloro-pyridin-3-yl)-2-hydroxy-ethyl Ester

[0311] To a cooled 5° C., stirred solution of(R)-1-(6-chloro-pyridin-3-yl)-ethane-1,2-diol (17.8 grams) in anhydrouspyridine (100 mL) was added p-toluenesulfonyl chloride (19.5 grams) inone portion. After 20 minutes, the cooling bath was removed and stirringwas continued an additional 12 hours. The reaction solution wasconcentrated in vacuo, azeotroped with toluene (2 times), diluted ethylacetate, washed with half-saturated aqueous brine, saturated aqueousbrine, dried over sodium sulfate and concentrated in vacuo. Theresulting solids were recrystallized from ethyl acetate/hexanes toafford the title compound as colorless crystals, 23.3 grams ¹H NMR (400MHz, CDCl₃)=8.29 (s, 1H); 7.72 (d, 2H); 7.64 (d, 1H); 7.32 (d, 2H); 7.28(d, 1H); 5.00 (dd, 1H); 4.09 (AB pattern, 2H); 2.44 (s, 3H).

EXAMPLE 5 (R)-Toluene-4-sulfonic Acid2-(tert-butyl-dimethyl-silanyloxy)-2-(6-chloro-Pyridin-3-yl)-ethel Ester

[0312] To a cooled 5° C., stirred solution of (R)-toluene-4-sulfonicacid 2-(6-chloro-pyridin-3-yl)-2-hydroxy-ethyl ester (4.9 grams) andimidazole (2.0 grams) in anhydrous dimethylormamide (14 mL) was addedt-butyldimethylsilyl chloride (2.8 grams). The mixture was allowed towarm to room temperature and stirring was continued for 18 hours. Ethylacetate was added, followed by washing with water (2 times), drying oversodium sulfate and concentrating in vacuo to afford an oil.Chromatography (Flash 40M®) utilizing 10% ethyl acetate/hexanes affordedthe title compound as a colorless oil, 5.6 grams ¹H NMR (400 MHz,CDCl₃): δ=8.24 (s, 1H); 7.64 (d, 2H); 7.56 (d, 1H); 7.28 (d, 2H); 7.23(d, 1H); 4.88 (dd, 1H); 3.95 (AB pattern, 2H); 2.44 (s, 3H); 0.83 (s,6H); 0.06 (s, 3H); −0.07 (s, 3H).

EXAMPLE 6[2r-(tert-Butyl-dimethylsilanyloxy)-2-(6-chloro-pyridin-3-yl)-ethyl]-[2-(4-nitrophenyl-ethyl]-carbamicAcid Tert-Butyl Ester

[0313] A solution of (R)-toulene-4-sulfonic acid2-(tert-butyl-dimethyl-silanyloxy)-2-(6-chloro-pyridin-3-yl)-etyl ester(2.2 grams), 4-nitrophenethylamine (1.6 grams) andN,N-diisopropylethylamine (0.8 grams) in DMSO were heated at 80° C. for7 hours. After cooling, di-t-butyl dicarbonate (2.1 grams) was added andthe resulting solution was stirred at ambient temperature for 4 hours.Ethyl acetate was added, followed by washing with water (2 times),drying over sodium sulfate and concentrating in vacuo to afford oil.Chromatography (Flash 12S®) utilizing 5-10% ethyl acetate/hexanesafforded the title compound as a colorless oil, 1.2.

EXAMPLE 7[2R-(4-Aminophenyl)-ethyl]-[2-(tert-butyl-dimethylsilanyloxy)-2-pyridin-3-yl-ethyl]-carbamicAcid Tert-Butyl Ester

[0314] To a stirred solution of[2-(tert-butyl-dimethylsilanyloxy)-2-(6-chloro-pyridin-3-yl)-ethyl]-[2-(4-nitrophenyl)-ethyl]-carbamicacid tert-butyl ester (0.6 grams) and ammonium formate (1.4 grams) inmethanol (10 mL) was added 10% palladium-on-carbon (0.6 grams). After 2hours, the mixture was filtered through Celite®, the filtrateconcentrated in vacuo and the residue partitioned between ethyl acetateand water. The organic phase was washed with brine, dried over sodiumsulfate and concentrated in vacuo to afford the title compound as ayellow oil, 0.5 grams.

1. A process for preparing a compound of the formula

wherein n is 0, 1, 2 or 3; R¹ is hydrogen or halo; each R² isindependently hydrogen, halo, trifluoromethyl, cyano, SR⁴, OR⁴, SO₂R⁴,OCOR⁵, or (C₁-C₁₀)alkyl wherein the alkyl group is optionallysubstituted by hydroxy, halo, cyano, N(R⁴)₂, SR⁴, trifluoromethyl, OR⁴,(C₃-C₈)cycloalkyl, (C₆-C₁₀)aryl, NR⁴COR⁵, COR⁵, SO₂R⁵, OCOR⁵, NR⁴SO₂R⁵and NR⁴CO₂ R⁴; R³ is tetrahydrofuranyl, tetrahydropyranyl or a silylprotecting group; X is halo, methanesulfonyloxy, benzenesulfonyloxy,p-toluenesulfonyloxy, m-nitrobenzenesulfonyloxy orp-nitrobenzenexulfonyloxy; R⁴ and R⁵, for each occurrence, are eachindependently selected from hydrogen, (C₁-C₁₀)alkyl, (C₁-C₁₀)alkoxy,(C₃-C₈)cycloalkyl,(C₆-C₁₀)aryl, (C₂-C₉)heterocycloalkyl,(C₂-C₉)heteroaryl or (C₁-C₆)aryl wherein the alkyl group is optionallysubstituted by the group consisting of hydroxy, halo, carboxy,(C₁-C₁₀)alkyl-CO₂, (C₁-C₁₀)alkylsulfonyl, (C₃-C₈)cycloalkyl,(C₁-C₁₀)alkoxy, or (C₁-C₆)alkyl; and wherein the aryl, heterocycloalkyland heteroaryl groups are optionally substituted by one to four groupsconsisting of halo, nitro, oxo, ((C₁-C₆)alkyl)₂amino, pyrrolidine,piperidine, (C₁-C₁₀)alkyl, (C₁-C₁₀)alkoxy, (C₁-C₁₀)alkylthio and(C₁-C₁₀)alkyl wherein the alkyl group is optionally substituted by oneto four groups selected from hydroxy, halo, carboxy, (C₁-C₆)alkyl-CO₂,(C₁-C₆)alkylsulfonyl, (C₃-C₈)cycloalkyl and (C₁-C₆)alkoxy; or R⁵ isN(R⁴)₂ wherein R⁴ is as defined above; comprising reacting a compound ofthe formula

wherein n, R¹, R² and X are as defined above, with a silyating agent inthe presence of a base.
 2. A process according to claim 1, wherein thesilyating agent is tert butyldimethylsilyl chloride,triethylchlorosilane, triisopropylchlorosilane ordiphenylmethylchlorosilane.
 3. A process according to claim 1, whereinthe base is triethylamine, N,N-diisopropylethylamine, imidazole,pyridine, 2,6-lutidine or N-methylmorpholine.
 4. A process according toclaim 1, wherein the compound of the formula

is formed by reacting a compound of the formula

wherein n, R¹ and R² are as defined above, with a sulfonyl chloride inthe presence of a base, and in the case wherein X is halo, by furthertreatment with a metal halide.
 5. A process according to claim 4,wherein the sulfonyl chloride is p-toluenesulfonyl chloride,methanesulfonyl chloride, m-nitrobenzenesulfonyl chloride,p-nitrobenzenesulfonyl chloride or benezenesulfonyl chloride.
 6. Aprocess according to claim 4, wherein the base is triethylamine,diisopropylethylamine, pyridine, 2,4,6-collidine or 2,6-lutidine.
 7. Aprocess according to claim 4, wherein the metal halide is lithiumchloride.
 8. A process according to claim 4, wherein the compound of theformula

is formed by reacting a compound of the formula

wherein n, R¹ and R² are as defined above, with a dihydroxylating agent,with or without a co-oxidant and/or a coordinating ligand.
 9. A processaccording to claim 8, wherein the dihydroxylating agent is osmiumtetroxide or potassium permanganate.
 10. A process according to claim 8,wherein the co-oxidant is potassium ferricyanide, hydrogen peroxide,tert-butyl hydroperoxide or N-methylmorpholine-N-oxide.
 11. A processaccording to claim 8, wherein the coordinating ligand is hydroquinidine1,4-phthalazinediyl diether or hydroquinine 1,4-phthalazinediyl diether.12. A process according to claim 8, wherein the compound of the formula

is formed by reacting a compound of formula V

wherein n, R¹ and R² are as defined above, with a methylating reagent.13. A process according to claim 12, wherein the methylating reagant isprepared from methyltriphenylphosphonium bromide and potassiumtert-butoxide.
 14. A process according to claim 12, wherein the compoundof the formula

is formed by reducing a compound of the formula

wherein n, R¹ and R² are as defined above, with a reducing agentfollowed by hydrolysis with an acid or base.
 15. A process according toclaim 14, wherein the reducing agent is diisobutylaluminum hydride. 16.A process according to claim 14, wherein the acid is sulfuric acid. 17.A process for preparing a compound of the formula

wherein n is 0, 1, 2 or 3; R¹ is hydrogen or halo; each R² isindependently hydrogen, halo, trifluoromethyl, cyano, SR⁴, OR⁴, SO₂R⁴,OCOR⁵, or (C₁-C₁₀)alkyl wherein the alkyl group is optionallysubstituted by hydroxy, halo, cyano, N(R⁴)₂, SR⁴, trifluoromethyl, OR⁴,(C₃-C₈)cycloalkyl, (C₆-C₁₀)aryl, NR⁴COR⁵, COR⁵, SO₂R⁵, OCOR⁵, NR⁴SO₂R⁵and NR⁴CO₂ R⁴; R³ is tetrahydrofuranyl, tetrahydropyranyl or a silylprotetcting group; X is halo, methanesulfonyloxy, benzenesulfonyloxy,p-toluenesulfonyloxy, m-nitrobenzenesulfonyloxy orp-nitrobenzenexulfonyloxy; R⁴ and R⁵, for each occurrence, are eachindependently selected from hydrogen, (C₁-C₁₀)alkyl,(C₁-C₁₀)alkoxy,(C₃-C₈)cycloalkyl,(C₆-C₁₀)aryl, (C₂-C₉)heterocycloalkyl,(C₂-C₉)heteroaryl or (C₁-C₆)aryl wherein the alkyl group is optionallysubstituted by the group consisting of hydroxy, halo, carboxy,(C₁-C₁)alkyl-CO₂, (C₁-C₁₀)alkylsulfonyl, (C₃-C₈)cycloalkyl,(C₁-C₁₀)alkoxy, or (C₁-C₆)alkyl; and wherein the aryl, heterocycloalkyland heteroaryl groups are optionally substituted by one to four groupsconsisting of halo, nitro, oxo, ((C₁-C₆)alkyl)₂amino, pyrrolidine,piperidine, (C₁-C₁₀)alkyl, (C₁-C₁₀)alkoxy, (C₁-C₁₀)alkylthio and(C₁-C₁₀)alkyl wherein the alkyl group is optionally substituted by oneto four groups selected from hydroxy, halo, carboxy, (C₁-C₆)alkyl-CO₂,(C₁-C₆)alkylsulfonyl, (C₃-C₈)cycloalkyl and (C₁-C₆)alkoxy; or R⁵ isN(R⁴)₂ wherein R⁴ is as defined above; comprising (a) reacting acompound of the formula

wherein n, R¹ and R² as defined above, with a reducing agent followed byhydrolsis with an acid or base; (b) reacting the intermediate of formulaXIII so formed

wherein n, R¹ and R² are as defined above, with a methylating agent toform a vinylpyridine compound of the formula

(c) reacting the vinylpyridine compound so formed in step (b) with adihydroxylating agent, with or without a co-oxidant and/or acoordinating ligand to form the compound of the formula

wherein n, R¹ and R² are as defined above; (d) reacting the compound offormula XI so formed with a sulfonyl chloride in the presence of a baseto form the compound of the formula X

wherein n, R¹, R² and X are as defined above; and (e) reacting thecompound of formula X so formed with silyating agent in the presence ofa base.
 18. A process for preparing a compound of the formula

wherein n is 0, 1, 2 or 3; each R² is independently hydrogen, halo,trifluoromethyl, cyano, SR⁴, OR⁴, SO₂R⁴, OCOR⁵, or (C₁-C₁₀)alkyl whereinthe alkyl group is optionally substituted by hydroxy, halo, cyano,N(R⁴)₂, SR⁴, trifluoromethyl, OR⁴, (C₃-C₈)cycloalkyl, (C₆-C₁₀)aryl,NR⁴COR⁵, COR⁵, SO₂R⁵, OCOR⁵, NR⁴SO₂R⁵ and NR⁴CO₂ R⁴; R⁴ and R⁵, for eachoccurrence, are each independently selected from hydrogen,(C₁-C₁₀)alkyl, (C₁-C₁₀)alkoxy, (C₃-C₈)cycloalkyl,(C₆-C₁₀)aryl,(C₂-C₉)heterocycloalkyl, (C₂-C₉)heteroaryl or (C₁-C₆)aryl wherein thealkyl group is optionally substituted by the group consisting ofhydroxy, halo, carboxy, (C₁-C₁₀)alkyl-CO₂, (C₁-C₁₀)alkylsulfonyl,(C₃-C₈)cycloalkyl, (C₁-C₁₀)alkoxy, or (C₁-C₆)alkyl; and wherein thearyl, heterocycloalkyl and heteroaryl groups are optionally substitutedby one to four groups consisting of halo, nitro, oxo,((C₁-C₆)alkyl)₂amino, pyrrolidine, piperidine, (C₁-C₁₀)alkyl,(C₁-C₁₀)alkoxy, (C₁-C₁₀)alkylthio and (C₁-C₁₀)alkyl wherein the alkylgroup is optionally substituted by one to four groups selected fromhydroxy, halo, carboxy, (C₁-C₆)alkyl-CO₂, (C₁-C₆)alkylsulfonyl,(C₃-C₈)cycloalkyl and (C₁-C₆)alkoxy; or R⁵ is N(R⁴)₂ wherein R⁴ is asdefined above; R⁶ is COR⁷ or CO₂R⁷ wherein R⁷ is (C₁-C₈)alkyl; and Y is

wherein: Q¹ is oxygen, nitrogen or sulfur; Q² is carbon or nitrogen; Q³is hydrogen, —(CH₂)_(q)-phenyl, —(C₁-C₁₀)alkyl, —(CH₂)_(q)—NG¹G²,—(CH₂)_(q)—CO₂G³, (CH₂)_(q)CONG¹G², (CH₂)_(q)OG³, (CH₂)_(q)SO₃G³,—(CH₂)_(q)—SO₂—(C₁-C₆)alkyl, —(CH₂)_(q)—SO₂NG¹G², or a heterocycleselected from the group consisting of —(CH₂)_(q)-pyridyl,—(CH₂)_(q)-pyrimidyl, —(CH₂)_(q)-pyraziqyl, —(CH₂)_(q)-isoxazolyl,—(CH₂)_(q)-oxazolyl, —(CH₂)_(q)-thiazolyl,—(CH₂)_(q)-(1,2,4-oxadiazolyl), —(CH₂)_(q)-imidazolyl,—(CH₂)_(q)-triazolyl and —(CH₂)_(q)-tetrazolyl; wherein one of the ringnitrogen atoms of said —(CH₂)_(q)-imidazolyl, —(CH₂)_(q)-triazolyl and—(CH₂)_(q)-tetrazolyl may optionally be substituted by (C₁-C₈)alkyloptionally independently substituted with one or more halo atoms;wherein each of said heterocycles may optionally be substituted on oneor more of the ring carbon atoms by one or more substituentsindependently selected from the group consisting of (C₁-C₈)alkyloptionally independently substituted with one or more halo atoms, nitro,cyano, —(CH₂)_(q)—NG¹G², —(CH₂)_(q)—CO₂G³, —(CH₂)_(q)—CO-NG¹G²,(CH₂)_(q)—OG³, (CH₂)_(q)—SO₃G³, —(CH₂)_(q)—SO₂-(C₁-C₆)alkyl and—(CH₂)_(q)—SO₂NG¹G²; wherein the phenyl moiety of said —(CH₂)_(q)-phenylmay optionally be substituted with one or more substituentsindependently selected from the group consisting of (C₁-C₆)alkyloptionally independently substituted with one or more halo atoms,hydroxy, (C₁-C₆)alkoxy optionally independently substituted with one ormore halo atoms, (C₁-C₆)alkylthio, fluoro, chloro, bromo, iodo, cyano,nitro, —(CH₂)_(q)—NG¹G², (CH₂)_(q)CO₂G³, (CH₂)_(q)CO—NG¹G²,(CH₂)_(q)—OG³, (CH₂)_(q)SO₃G³, (CH₂)_(q)SO₂—(C₁-C₆)alkyl,—(CH₂)_(q)—SO₂NG¹G²; —(CH₂)_(q)—NG³—SO₂-G³ and —(CH₂)_(q)—NG³—SO₂—NG¹G²;Q⁴ is —(CH₂)_(q)—CN, —(CH₂)_(q)CO₂G³, —(CH₂)_(q)—SO₃G³,—(CH₂)_(q)—SO₂—(C₁-C₆)alkyl, (CH₂)_(q)SO₂NG¹G², —(CH₂)_(q)CH₂OH,(CH₂)_(q)CHO, (CH₂)_(q)COG³, (CH₂)_(q)—CONG¹G², or a heterocycleselected from —(CH₂)_(q)-thiazolyl, —(CH₂)_(q)-oxazolyl,—(CH₂)_(q)-imidazolyl, —(CH₂)_(q)-triazolyl,——(CH₂)_(q)-1,2,4-oxadiazolyl, —(CH₂)_(q)-isoxazolyl,—(CH₂)_(q)-tetrazolyl and —(CH₂)_(q)-pyrazolyl; wherein one of the ringnitrogen atoms of said —(CH₂)_(q)-imidazolyl, —(CH₂)_(q)-triazolyl and—(CH₂)_(q)-tetrazolyl may optionally be substituted by (C₁-C₆)alkyloptionally independently substituted with one or more halo atoms;wherein each of said heterocycles may optionally be substituted on oneor more of the ring carbon atoms by one or more substituentsindependently selected from the group consisting of hydrogen,(C₁-C₆)alkyl optionally independently substituted with one or more haloatoms, —(CH₂)_(q)—CO-NG¹G², —(CH₂)_(q)—CO₂G³, halo, nitro, cyano,—(CH₂)_(q)—CO-NG¹G², —(CH₂)_(q)—OG³, —(CH₂)_(q)—SO₃G³,—(CH₂)_(q)SO₂—(C₁-C₆)alkyl, or —(CH₂)_(q)—SO₂NG¹G²; Q⁵ is hydrogen or(C₁-C₆)alkyl optionally independently substituted with one or more haloatoms; Q⁶ is a covalent bond, oxygen or sulfur; Q⁷ is hydrogen or(C₁-C₆)alkyl optionally independently substituted with one or more haloatoms; Q⁸ and Q⁹ are independently a covalent bond, oxygen, sulfur, NHor N-(C₁-C₆)alkyl; Q¹⁰ is nitro, amino, (C₂-C₉)heteroaryl,(C₂-C₉)heterocycloalkyl, (CH₂)_(p)OR¹¹, (CH₂)_(q)CO₂H, (CH₂)_(q)COR¹³,(CH₂)_(q)SO₂NR¹¹R¹², (CH₂)_(q)—NR¹¹SO₂R¹⁰, (CH₂)_(q)P(O)(OR⁸)(OR⁹),(CH₂)_(q)O(CH₂)_(p)CO₂H, (CH₂)_(q)O(CH₂)_(p)COR¹³,(CH₂)_(q)—O—(CH₂)_(p)P(O)(OR⁸)(OR⁹), (CH₂)_(q)—O—(CH₂)_(p)SO₂NR¹¹R², or(CH₂)_(q)O(CH₂)_(p)—NR¹¹SO₂R¹⁰; R⁸ and R⁹ are each independentlyhydrogen or (C₁-C₆)alkyl; and wherein G¹ and G² for each occurrence areeach independently hydrogen, (C₁-C₆)alkyl optionally independentlysubstituted with one or more halo, (C₁-C₈)alkoxy(C₁-C₆)alkyl or(C₃-C₈)cycloalkyl, or G¹ and G² together with the nitrogen to which theyare attached form a saturated heterocyclic ring having from 3 to 7carbon atoms wherein one of said carbon atoms may optionally be replacedby oxygen, nitrogen or sulfur; G³ for each occurrence is independentlyhydrogen or (C₁-C₆)alkyl; R¹⁰ for each occurrence is independently(C₁-C₆)alkyl or (C₁-C₆)alkoxy(C₁-C₆)alkyl; R¹¹ and R¹² are takenseparately and, for each occurrence, are independently hydrogen,(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, or (C₁-C₆)alkoxy(C₁-C₆)alkyl, or R¹¹and R¹² are taken together with the nitrogen atom to which they areattached and form a pyrrolidine, piperidine or morpholine ring whereinsaid pyrrolidine, piperidine or morpholine may optionally be substitutedat any carbon atom by (C₁-C₄)alkyl or (C₁-C₄)alkoxy; R¹³ for eachoccurrence is independently hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,NR¹¹R¹², (C₃-C₈)cycloalkyl, or (C₁-C₆)alkoxy(C₁-C₆)alkyl wherein R¹¹ andR¹² are as defined above; R¹⁴ and R¹⁵ are each independently hydrogen,halo, (C₁-C₆)alkyl, nitro, cyano, trifluoromethyl, SO₂R¹⁰, SO₂NR¹¹R¹²,NR¹¹R¹², COR¹³, CO₂R¹¹, (C₁-C₆)alkoxy, NR¹¹SO₂R¹⁰, NR¹¹COR¹³, NR¹¹CO₂R¹¹or OR¹¹; p for each occurrence is independently an integer of 1 to 6;and q for each occurrence is independently 0 or an integer of 1 to 6;with the proviso that when Q⁹ is O or S then n is not 0; with theproviso that when Q¹ is oxygen or sulfur then Q³ is absent; and with theproviso that when Q² is nitrogen then Q⁵ is absent; comprising reactinga compound of the formula

wherein n, R², R⁶ and Y are as defined above; and R³ istetrahydrofuranyl, tetrahydropyranyl or a silyl protecting group; withtetra-n-butylammonium fluoride.
 19. A process according to claim 18,wherein the compound of the formula

wherein n, R², R³, R⁶ and Y are as defined above, is formed by treatinga compound of the formula

wherein R¹ is halo and wherein n, R², R³, R⁶ and Y are as defined above,with ammonium formate in the presence of palladium on carbon.
 20. Aprocess according to claim 19, wherein the compound of the formula

is formed by reacting the compound

wherein R¹ is hydrogen or halo and wherein n, R², R³ and Y are asdefined above with an organic acid anhydride, a dicarbonate or anorganic acid chloride.
 21. A process according to claim 20, wherein thedicarbonate is di-tert-butyl dicarbonate
 22. A process according toclaim 20, wherein the compound

is formed by reacting the compound

wherein n, R¹, R², R³ and X are as defined above, with an amine of theformula H₂NY, wherein Y is as defined above, in the presence of NN-diisopropylethylamine.
 23. A process for preparing a compound of theformula

wherein n is 0, 1, 2 or 3; each R² is independently hydrogen, halo,trifluoromethyl, cyano, SR⁴, OR⁴, SO₂R⁴, OCOR⁵, or (C₁-C₁₀)alkyl whereinthe alkyl group is optionally substituted by hydroxy, halo, cyano,N(R⁴)₂, SR⁴, trifluoromethyl, OR⁴, (C₃-C₈)cycloalkyl, (C₆-C₁₀)aryl,NR⁴COR⁵, COR⁵, SO₂R⁵, OCOR⁵, NR⁴SO₂R⁵ and NR⁴CO₂ R⁴; R⁴ and R⁵, for eachoccurrence, are each independently selected from hydrogen,(C₁-C₁₀)alkyl, (C₁-C₁₀)alkoxy, (C₃-C₈)cycloalkyl,(C₆-C₁₀)aryl,(C₂-C₉)heterocycloalkyl, (C₂-C₉)heteroaryl or (C₁-C₆)aryl wherein thealkyl group is optionally substituted by the group consisting ofhydroxy, halo, carboxy, (C₁-C₁₀)alkyl-CO₂, (C₁-C₁₀)alkylsulfonyl,(C₃-C₈)cycloalkyl, (C₁-C₁₀)alkoxy, or (C₁-C₆)alkyl; and wherein thearyl, heterocycloalkyl and heteroaryl groups are optionally substitutedby one to four groups consisting of halo, nitro, oxo,((C₁-C₆)alkyl)₂amino, pyrrolidine, piperidine, (C₁-C₁₀)alkyl,(C₁-C₁₀)alkoxy, (C₁-C₁₀)alkylthio and (C₁-C₁₀)alkyl wherein the alkylgroup is optionally substituted by one to four groups selected fromhydroxy, halo, carboxy, (C₁-C₆)alkyl-CO₂, (C₁-C₆)alkylsulfonyl,(C₃-C₈)cycloalkyl and (C₁-C₆)alkoxy; or R⁵ is N(R⁴)₂ wherein R⁴ is asdefined above; R⁶ is COR⁷ or CO₂R⁷ wherein R⁷ is (C₁-C₈)alkyl; and Y is

wherein: Q¹ is oxygen, nitrogen or sulfur; Q² is carbon or nitrogen; Q³is hydrogen, —(CH₂)_(q)-phenyl, —(C₁-C₁₀)alkyl, —(CH₂)_(q)—NG¹G²,—(CH₂)_(q)—CO₂G³, (CH₂)_(q)CO—NG¹G², —(CH₂)_(q)OG³, (CH₂)_(q)SO₃G³,—(CH₂)_(q)—SO₂—(C₁-C₆)alkyl, —(CH₂)_(q)—SO₂NG¹G², or a heterocycleselected from the group consisting of —(CH₂)_(q)-pyridyl,—(CH₂)_(q)-pyrimidyl, —(CH₂)_(q)-pyraziqyl, —(CH₂)_(q)-isoxazolyl,—(CH₂)_(q)-oxazolyl, —(CH₂)_(q)-thiazolyl,—(CH₂)_(q)-(1,2,4-oxadiazolyl), —(CH₂)_(q)-imidazolyl,—(CH₂)_(q)-triazolyl and —(CH₂)_(q)-tetrazolyl; wherein one of the ringnitrogen atoms of said —(CH₂)_(q)-imidazolyl, —(CH₂)_(q)-triazolyl and—(CH₂)_(q)-tetrazolyl may optionally be substituted by (C₁-C₈)alkyloptionally independently substituted with one or more halo atoms;wherein each of said heterocycles may optionally be substituted on oneor more of the ring carbon atoms by one or more substituentsindependently selected from the group consisting of (C₁-C₈)alkyloptionally independently substituted with one or more halo atoms, halo,nitro, cyano, —(CH₂)_(q)—NG¹G², —(CH₂)_(q)—CO₂G³, —(CH₂)_(q)CO NG¹G²,(CH₂)_(q0)G³, (CH₂)_(q)SO₃G³—(CH₂)_(q)—SO₂-(C₁-C₆)alkyl and—(CH₂)_(q)—SO₂NG¹G²; wherein the phenyl moiety of said —(CH₂)_(q)-phenylmay optionally be substituted with one or more substituentsindependently selected from the group consisting of (C₁-C₆)alkyloptionally independently substituted with one or more halo atoms,hydroxy, (C₁-C₆)alkoxy optionally independently substituted with one ormore halo atoms, (C₁-C₆)alkylthio, fluoro, chloro, bromo, iodo, cyano,nitro, —(CH₂)_(q)—NG¹G², —(CH₂)_(q)—CO₂G³, —(CH₂)_(q)—CO—NG¹G²,—(CH₂)_(q)—OG³, (CH₂)_(q)SO₃G³, —(CH₂)_(q)SO₂—(C₁-C₆)alkyl,—(CH₂)_(q)—SO₂NG¹G²; —(CH₂)_(q)—NG³_SO₂-G³ and —(CH₂)_(q)—NG³—SO₂—NG¹G²;Q⁴ is (CH₂)_(q)CN, (CH₂)_(q)CO₂G³, (CH₂)_(q)SO₃G³,—(CH₂)_(q)SO₂(C₁-C₆)alkyl, (CH₂)_(q)SO₂NG¹G², (CH₂)_(q)CH₂OH,(CH₂)_(q)CHO, (CH₂)_(q)COG³, (CH₂)_(q)CONG¹G², or a heterocycle selectedfrom —(CH₂)_(q)-thiazolyl, —(CH₂)_(q)-oxazolyl, —(CH₂)_(q)-imidazolyl,—(CH₂)_(q)-triazolyl, —(CH₂)_(q)-1,2,4-oxadiazolyl,—(CH₂)_(q)-isoxazolyl, —(CH₂)_(q)-tetrazolyl and —(CH₂)_(q)-pyrazolyl;wherein one of the ring nitrogen atoms of said —(CH₂)_(q)-imidazolyl,—(CH₂)_(q)-triazolyl and —(CH₂)_(q)-tetrazolyl may optionally besubstituted by (C₁-C₆)alkyl optionally independently substituted withone or more halo atoms; wherein each of said heterocycles may optionallybe substituted on one or more of the ring carbon atoms by one or moresubstituents independently selected from the group consisting ofhydrogen, (C₁-C₆)alkyl optionally independently substituted with one ormore halo atoms, —(CH₂)_(q)—CO-NG¹G², —(CH₂)_(q)—CO₂G³, halo, nitro,cyano, —(CH₂)_(q)—CO-NG¹G², —(CH₂)_(q)—OG³, (CH₂)_(q)SO₃G³,(CH₂)_(q)SO₂—(C₁-C₆)alkyl, or —(CH₂)_(q)—SO₂NG¹G²; Q⁵ is hydrogen or(C₁-C₆)alkyl optionally independently substituted with one or more haloatoms; Q⁶ is a covalent bond, oxygen or sulfur; Q⁷ is hydrogen or(C₁-C₆)alkyl optionally independently substituted with one or more haloatoms; Q⁸ and Q⁹ are independently a covalent bond, oxygen, sulfur, NHor N-(C₁-C₆)alkyl; Q¹⁰ is nitro, amino, (C₂-C₉)heteroaryl,(C₂-C₉)heterocycloalkyl, (CH₂)_(p)OR¹¹, (CH₂)_(q)CO₂H, (CH₂)_(q)COR¹³,(CH₂)_(q)SO₂NR¹¹R¹², (CH₂)_(q)NR¹¹SO₂R¹⁰, (CH₂)_(q)P(O)(OR⁸)(OR⁹),(CH₂)_(q)O(CH₂)_(p)CO₂H, (CH₂)_(q)O(CH₂)_(p)COR¹³,(CH₂)_(q)—O—(CH₂)_(p)P(O)(OR⁸)(OR⁹), (CH₂)_(q)—O—(CH₂)_(p)SO₂NR¹¹R¹², or(CH₂)_(q)—O—(CH₂)_(p)—NR¹¹SO₂R¹⁰; R⁸ and R⁹ are each independentlyhydrogen or (C₁-C₆)alkyl; and wherein G¹ and G² for each occurrence areeach independently hydrogen, (C₁-C₆)alkyl optionally independentlysubstituted with one or more halo, (C₁-C₈)alkoxy(C₁-C₆)alkyl or(C₃-C₈)cycloalkyl, or G¹ and G² together with the nitrogen to which theyare attached form a saturated heterocyclic ring having from 3 to 7carbon atoms wherein one of said carbon atoms may optionally be replacedby oxygen, nitrogen or sulfur; G³ for each occurrence is independentlyhydrogen or (C₁-C₆)alkyl; R¹⁰ for each occurrence is independently(C₁-C₆)alkyl or (C₁-C₆)alkoxy(C₁-C₆)alkyl; R¹¹ and R¹² are takenseparately and, for each occurrence, are independently hydrogen,(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, or (C₁-C₆)alkoxy(C₁-C₆)alkyl, or R¹¹and R¹² are taken together with the nitrogen atom to which they areattached and form a pyrrolidine, piperidine or morpholine ring whereinsaid pyrrolidine, piperidine or morpholine may optionally be substitutedat any carbon atom by (C₁-C₄)alkyl or (C₁-C₄)alkoxy; R¹³ for eachoccurrence is independently hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,NR¹R¹², (C₃-C₈)cycloalkyl, or (C₁-C₆)alkoxy(C₁-C₆)alkyl wherein R¹¹ andR¹² are as defined above; R¹⁴ and R¹⁵ are each independently hydrogen,halo, (C₁-C₆)alkyl, nitro, cyano, trifluoromethyl, SO₂R¹⁰, SO₂NR¹¹R²,NR¹¹R², COR³, CO₂R¹¹, (C₁-C₆)alkoxy, NR¹¹SO₂R¹⁰, NR¹¹COR¹³, NR¹¹CO₂R¹¹or OR¹¹; p for each occurrence is independently an integer of 1 to 6;and q for each occurrence is independently 0 or an integer of 1 to 6;with the proviso that when Q⁹ is O or S then n is not 0; with theproviso that when Q¹ is oxygen or sulfur then Q³ is absent; and with theproviso that when Q² is nitrogen then Q⁵ is absent; comprising (a)reacting a compound of the formula

wherein R¹ is hydrogen or halo, and n, R¹, R², R³ and X are as definedabove, with an amine of the formula H₂NY, wherein Y is as defined abovein the presence of N,N-diisopropylethylamine; (b) reacting the compoundof formula IV so formed

wherein R¹ is hydrogen or halo and wherein n, R², R³ and Y are asdefined above with an organic acid anhydride, a dicarbonate or anorganic acid chloride, to form a compound of the formula

(c) treating the compound of formula II, wherein R¹ is halo, so formedin step (b) with ammonium formate in the presence of palladium-on-carbonto form the compound of the formula

wherein n, R², R³, R⁶ and Y are as defined above, and (d) treating thecompound of formula II so formed with tetra-n-butylammonium fluoride.24. A process for preparing a compound of the formula

wherein n is 0, 1, 2 or 3; each R² is independently hydrogen, halo,trifluoromethyl, cyano, SR⁴, OR⁴, SO₂R⁴, OCOR⁵, or (C₁-C₁₀)alkyl whereinthe alkyl group is optionally substituted by hydroxy, halo, cyano,N(R⁴)₂, SR⁴, trifluoromethyl, OR⁴, (C₃-C₈)cycloalkyl, (C₆-C₁₀)aryl,NR⁴COR⁵, COR⁵, SO₂R⁵, OCOR⁵, NR⁴SO₂R⁵ and NR⁴CO₂ R⁴; R⁴ and R⁵, for eachoccurrence, are each independently selected from hydrogen,(C₁-C₁₀)alkyl, (C₁-C₁₀)alkoxy, (C₃-C₈)cycloalkyl,(C₆-C₁₀)aryl,(C₂-C₉)heterocycloalkyl, (C₂-C₉)heteroaryl or (C₁-C₆)aryl wherein thealkyl group is optionally substituted by the group consisting ofhydroxy, halo, carboxy, (C₁-C₁₀)alkyl-CO₂, (C₁-C₁₀)alkylsulfonyl,(C₃-C₈)cycloalkyl, (C₁-C₁₀)alkoxy, or (C₁-C₆)alkyl; and wherein thearyl, heterocycloalkyl and heteroaryl groups are optionally substitutedby one to four groups consisting of halo, nitro, oxo,((C₁-C₆)alkyl)₂amino, pyrrolidine, piperidine, (C₁-C₁₀)alkyl,(C₁-C₁₀)alkoxy, (C₁-C₁₀)alkylthio and (C₁-C₁₀)alkyl wherein the alkylgroup is optionally substituted by one to four groups selected fromhydroxy, halo, carboxy, (C₁-C₆)alkyl-CO₂, (C₁-C₆)alkylsulfonyl,(C₃-C₈)cycloalkyl and (C₁-C₆)alkoxy; or R⁵ is N(R⁴)₂ wherein R⁴ is asdefined above; R⁶ is COR⁷ or CO₂R⁷ wherein R⁷ is (C₁-C₈)alkyl; and Y is

wherein: Q¹ is oxygen, nitrogen or sulfur; Q² is carbon or nitrogen; Q³is hydrogen, —(CH₂)_(q)-phenyl, —(C₁-C₁₀)alkyl, —(CH₂)_(q)—NG¹G²,—(CH₂)_(q)—CO₂G³, (CH₂)_(q)CO—NG¹G², (CH₂)_(q)OG³, (CH₂)_(q)SO₃G³,(CH₂)_(q)SO₂(C₁-C₆)alkyl, —(CH₂)_(q)—SO₂NG¹G², or a heterocycle selectedfrom the group consisting of —(CH₂)_(q)-pyridyl, —(CH₂)_(q)-pyrimidyl,—(CH₂)_(q)-pyraziqyl, —(CH₂)_(q)-isoxazolyl, —(CH₂)_(q)-oxazolyl,—(CH₂)_(q)-thiazolyl, —(CH₂)_(q)-(1,2,4-oxadiazolyl),—(CH₂)_(q)-imidazolyl, —(CH₂)_(q)-triazolyl and —(CH₂)_(q)-tetrazolyl;wherein one of the ring nitrogen atoms of said —(CH₂)_(q)-imidazolyl,—(CH₂)_(q)-triazolyl and —(CH₂)_(q)-tetrazolyl may optionally besubstituted by (C₁-C₈)alkyl optionally independently substituted withone or more halo atoms; wherein each of said heterocycles may optionallybe substituted on one or more of the ring carbon atoms by one or moresubstituents independently selected from the group consisting of(C₁-C₈)alkyl optionally independently substituted with one or more haloatoms, nitro, cyano, —(CH₂)_(q)—NG¹G², —(CH₂)_(q)—CO₂G³,—(CH₂)_(q)—CO-NG¹G², (CH₂)_(q)OG³, —(CH₂)_(q)—SO₃G³,—(CH₂)_(q)—SO₂—(C₁-C₆)alkyl and —(CH₂)_(q)—SO₂NG¹G²; wherein the phenylmoiety of said —(CH₂)_(q)-phenyl may optionally be substituted with oneor more substituents independently selected from the group consisting of(C₁-C₆)alkyl optionally independently substituted with one or more haloatoms, hydroxy, (C₁-C₆)alkoxy optionally independently substituted withone or more halo atoms, (C₁-C₆)alkylthio, fluoro, chloro, bromo, iodo,cyano, nitro, —(CH₂)_(q)—NG¹G², (CH₂)_(q)CO₂G³, (CH₂)_(q)CONG¹G²,(CH₂)_(q)OG³, (CH₂)_(q)SO₃G³, (CH₂)_(q)SO₂—(C₁-C₆)alkyl,—(CH₂)_(q)—SO₂NG¹G²; —(CH₂)_(q)—NG³—SO₂-G³ and —(CH₂)_(q)—NG³_SO₂—NG¹G²;Q⁴ is (CH₂)_(q)CN, —(CH₂)_(q)CO₂G³, —(CH₂)_(q)—SO₃G³,—(CH₂)_(q)—SO₂-(C₁-C₆)alkyl, —(CH₂)_(q)SO₂NG¹G², (CH₂)_(q)CH₂OH,(CH₂)_(q)CHO, (CH₂)_(q)CO-G³, (CH₂)_(q)CONG¹G², or a heterocycleselected from —(CH₂)_(q)-thiazolyl, —(CH₂)_(q)-oxazolyl,—(CH₂)_(q)-imidazolyl, —(CH₂)_(q)-triazolyl,—(CH₂)_(q)-1,2,4-oxadiazolyl, —(CH₂)_(q)-isoxazolyl,—(CH₂)_(q)-tetrazolyl and —(CH₂)_(q)-pyrazolyl; wherein one of the ringnitrogen atoms of said —(CH₂)_(q)-imidazolyl, —(CH₂)_(q)-triazolyl and—(CH₂)_(q)-tetrazolyl may optionally be substituted by (C₁-C₆)alkyloptionally independently substituted with one or more halo atoms;wherein each of said heterocycles may optionally be substituted on oneor more of the ring carbon atoms by one or more substituentsindependently selected from the group consisting of hydrogen,(C₁-C₆)alkyl optionally independently substituted with one or more haloatoms, —(CH₂)_(q)—CO-NG¹G², —(CH₂)_(q)—CO₂G³, halo, nitro, cyano,—(CH₂)_(q)—CO-NG¹G², —(CH₂)_(q)—OG³, _(CH₂)_(q)—SO₃G³,—(CH₂)_(q)—SO₂—(C₁-C₆)alkyl, or —(CH₂)_(q)—SO₂NG¹G²; Q⁵ is hydrogen or(C₁-C₆)alkyl optionally independently substituted with one or more haloatoms; Q⁶ is a covalent bond, oxygen or sulfur; Q⁷ is hydrogen or(C₁-C₆)alkyl optionally independently substituted with one or more haloatoms; Q⁸ and Q⁹ are independently a covalent bond, oxygen, sulfur, NHor N-(C₁-C₆)alkyl; Q¹⁰ is nitro, amino, (C₂-C₉)heteroaryl,(C₂-C₉)heterocycloalkyl. (CH₂)_(p)OR¹¹, (CH₂)_(q)CO₂H, (CH₂)_(q)COR¹³,(CH₂)_(q)SO₂NR¹¹R², (CH₂)_(q)NR¹¹SO₂R¹⁰, (CH₂)_(q)P(O)(OR⁸)(OR⁹),(CH₂)_(q)—O—(CH₂)_(p)CO₂H, (CH₂)_(q)—O—(CH₂)_(p)COR¹³,—(CH₂)_(q)—O—(CH₂)_(p)P(O)(OR⁸)(OR⁹), (CH₂)_(q)—O—(CH₂)_(p)SO₂NR¹¹R¹²,or (CH₂)_(q)O(CH₂)_(p)—NR¹¹SO₂R¹⁰; R⁸ and R⁹ are each independentlyhydrogen or (C₁-C₆)alkyl; and wherein G¹ and G² for each occurrence areeach independently hydrogen, (C₁-C₆)alkyl optionally independentlysubstituted with one or more halo, (C₁-C₈)alkoxy(C₁-C₆)alkyl or(C₃-C₈)cycloalkyl, or G¹ and G² together with the nitrogen to which theyare attached form a saturated heterocyclic ring having from 3 to 7carbon atoms wherein one of said carbon atoms may optionally be replacedby oxygen, nitrogen or sulfur; G³ for each occurrence is independentlyhydrogen or (C₁-C₆)alkyl; R¹⁰ for each occurrence is independently(C₁-C₆)alkyl or (C₁-C₆)alkoxy(C₁-C₆)alkyl; R¹¹ and R¹² are takenseparately and, for each occurrence, are independently hydrogen,(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, or (C₁-C₆)alkoxy(C₁-C₆)alkyl, or R¹¹and R¹² are taken together with the nitrogen atom to which they areattached and form a pyrrolidine, piperidine or morpholine ring whereinsaid pyrrolidine, piperidine or morpholine may optionally be substitutedat any carbon atom by (C₁-C₄)alkyl or (C₁-C₄)alkoxy; R¹³ for eachoccurrence is independently hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,NR¹¹R², (C₃-C₈)cycloalkyl, or (C₁-C₆)alkoxy(C₁-C₆)alkyl wherein R¹¹ andR¹² are as defined above; R¹⁴ and R¹⁵ are each independently hydrogen,halo, (C₁-C₆)alkyl, nitro, cyano, trifluoromethyl, SO₂R¹⁰, SO₂NR¹¹R¹²,NR¹¹R¹², COR¹³, CO₂R¹¹, (C₁-C₆)alkoxy, NR¹¹SO₂R¹⁰, NR¹¹COR¹³, NR¹¹CO₂R¹¹or OR¹¹; p for each occurrence is independently an integer of 1 to 6;and q for each occurrence is independently 0 or an integer of 1 to 6;with the proviso that when Q⁹ is O or S then n is not 0; with theproviso that when Q⁹ is oxygen or sulfur then Q³ is absent; and with theproviso that when Q² is nitrogen then Q⁵ is absent; comprising reactinga compound of the formula

wherein R¹ is halo and wherein n, R², R³ and Y are as defined above,with ammonium formate in the presence of palladium-on-carbon.
 25. Aprocess according to claim 24, wherein the compound of the formula

is formed by reacting a compound of the formula

wherein R¹ is hydrogen or halo, and wherein n, R² and Y are as definedabove, with an organic acid anhydride, a dicarbonate or an organic acidchloride.
 26. A process according to claim 25, wherein the dicarbonateis di-tert-butyl dicarbonate
 27. A process according to claim 25,wherein the compound of the formula

is formed by reacting the compound

wherein n, R¹, R² and X are as defined above, with an amine of theformula H₂NY, wherein Y is as defined above, in the presence ofN,N-diisopropylethylamine.
 28. A process for preparing a compound of theformula

wherein n is 0, 1, 2 or 3; each R² is independently hydrogen, halo,trifluoromethyl, cyano, SR⁴, OR⁴, SO₂R⁴, OCOR⁵, or (C₁-C₁₀)alkyl whereinthe alkyl group is optionally substituted by hydroxy, halo, cyano,N(R⁴)₂, SR⁴, trifluoromethyl, OR⁴, (C₃-C₈)cycloalkyl, (C₆-C₁₀)aryl,NR⁴COR⁵, COR⁵, SO₂R⁵, OCOR⁵, NR⁴SO₂R⁵ and NR⁴CO₂ R⁴; R⁴ and R⁵, for eachoccurrence, are each independently selected from hydrogen,(C₁-C₁₀)alkyl, (C₁-C₁₀)alkoxy, (C₃-C₈)cycloalkyl,(C₆-C₁₀)aryl,(C₂-C₉)heterocycloalkyl, (C₂-C₉)heteroaryl or (C₁-C₆)aryl wherein thealkyl group is optionally substituted by the group consisting ofhydroxy, halo, carboxy, (C₁-C₁₀)alkyl-CO₂, (C₁-C₁₀)alkylsulfonyl,(C₃-C₈)cycloalkyl, (C₁-C₁₀)alkoxy, or (C₁-C₆)alkyl; and wherein thearyl, heterocycloalkyl and heteroaryl groups are optionally substitutedby one to four groups consisting of halo, nitro, oxo,((C₁-C₆)alkyl)₂amino, pyrrolidine, piperidine, (C₁-C₁₀)alkyl,(C₁-C₁₀)alkoxy, (C₁C₁₀)alkylthio and (C₁-C₁₀)alkyl wherein the alkylgroup is optionally substituted by one to four groups selected fromhydroxy, halo, carboxy, (C₁-C₆)alkyl-CO₂, (C₁-C₆)alkylsulfonyl,(C₃-C₈)cycloalkyl and (C₁-C₆)alkoxy; or R⁵ is N(R⁴)₂ wherein R⁴ is asdefined above; R⁶ is COR⁷ or CO₂R⁷ wherein R⁷ is (C₁-C₈)alkyl; and Y is

wherein: Q¹ is oxygen, nitrogen or sulfur; Q² is carbon or nitrogen; Q³is hydrogen, —(CH₂)_(q)-phenyl, —(C₁-C₁₀)alkyl, —(CH₂)_(q)—NG¹G²,—(CH₂)_(q)—CO₂G³, —(CH₂)_(q)—CO—NG¹G², —(CH₂)_(q)—OG³, —(CH₂)_(q)—SO₃G³,—(CH₂)_(q)—SO₂-(C₁-C₆)alkyl, —(CH₂)_(q)—SO₂NG¹G², or a heterocycleselected from the group consisting of —(CH₂)_(q)-pyridyl,—(CH₂)_(q)-pyrimidyl, —(CH₂)_(q)-pyraziqyl, —(CH₂)_(q)-isoxazolyl,(CH₂)_(q)-oxazolyl, —(CH₂)_(q)-thiazolyl,—(CH₂)_(q)-(1,2,4-oxadiazolyl), —(CH₂)_(q)-imidazolyl,—(CH₂)_(q)-triazolyl and —(CH₂)_(q)-tetrazolyl; wherein one of the ringnitrogen atoms of said —(CH₂)_(q)-imidazolyl, —(CH₂)_(q)-triazolyl and—(CH₂)_(q)-tetrazolyl may optionally be substituted by (C₁-C₈)alkyloptionally independently substituted with one or more halo atoms;wherein each of said heterocycles may optionally be substituted on oneor more of the ring carbon atoms by one or more substituentsindependently selected from the group consisting of (C₁-C₈)alkyloptionally independently substituted with one or more halo atoms, nitro,cyano, —(CH₂)_(q)—NG¹G², —(CH₂)_(q)—CO₂G³, —(CH₂)_(q)—CO-NG¹G²,—(CH₂)_(q)—OG³, —(CH₂)_(q)—SO₃G³, —(CH₂)_(q)—SO₂-(C₁-C₆)alkyl and—(CH₂)_(q)—SO₂NG¹G²; wherein the phenyl moiety of said —(CH₂)_(q)-phenylmay optionally be substituted with one or more substituentsindependently selected from the group consisting of (C₁-C₆)alkyloptionally independently substituted with one or more halo atoms,hydroxy, (C₁-C₆)alkoxy optionally independently substituted with one ormore halo atoms, (C₁-C₆)alkylthio, fluoro, chloro, bromo, iodo, cyano,nitro, —(CH₂)_(q)—NG¹G², —(CH₂)_(q)CO₂G³, (CH₂)_(q)CO—NG¹G²,(CH₂)_(q)OG³, (CH₂)_(q)SO₃G³, —(CH₂)_(q)—SO₂—(C₁-C₆)alkyl,—(CH₂)_(q)—SO₂NG¹G²; —(CH₂)_(q)—NG³_SO₂-G³ and —(CH₂)_(q)—NG³—SO₂—NG¹G²;Q⁴ is —(CH₂)_(q)—CN, —(CH₂)_(q)CO₂G³, —(CH₂)_(q)—SO₃G³,—(CH₂)_(q)—SO₂-(C₁-C₆)alkyl, —(CH₂)_(q)SO₂NG¹G², (CH₂)_(q)CH₂OH,—(CH₂)_(q)CHO, (CH₂)_(q)CO-G³, (CH₂)_(q)CONG¹G², or a heterocycleselected from —(CH₂)_(q)-thiazolyl, —(CH₂)_(q)-oxazolyl,—(CH₂)_(q)-imidazolyl, —(CH₂)_(q)-triazolyl,—(CH₂)_(q)-1,2,4-oxadiazolyl, —(CH₂)_(q)-isoxazolyl,—(CH₂)_(q)-tetrazolyl and —(CH₂)_(q)-pyrazolyl; wherein one of the ringnitrogen atoms of said —(CH₂)_(q)-imidazolyl, —(CH₂)_(q)-triazolyl and—(CH₂)_(q)-tetrazolyl may optionally be substituted by (C₁-C₆)alkyloptionally independently substituted with one or more halo atoms;wherein each of said heterocycles may optionally be substituted on oneor more of the ring carbon atoms by one or more substituentsindependently selected from the group consisting of hydrogen,(C₁-C₆)alkyl optionally independently substituted with one or more haloatoms, —(CH₂)_(q)—CO-NG¹G², —(CH₂)_(q)—CO₂G³, halo, nitro, cyano,—(CH₂)_(q)—CO—NG¹G², —(CH₂)_(q)—OG³, —(CH₂)_(q)—SO₃G³,(CH₂)_(q)—SO₂(C₁-C₆)alkyl, or —(CH₂)_(q)—SO₂NG¹G²; Q⁵ is hydrogen or(C₁-C₆)alkyl optionally independently substituted with one or more haloatoms; Q⁶ is a covalent bond, oxygen or sulfur; Q⁷ is hydrogen or(C₁-C₆)alkyl optionally independently substituted with one or more haloatoms; Q⁸ and Q⁹ are independently a covalent bond, oxygen, sulfur, NHor N—(C₁-C₆)alkyl; Q¹⁰ is nitro, amino, (C₂-C₉)heteroaryl,(C₂-C₉)heterocycloalkyl, (CH₂)_(p)OR¹¹, (CH₂)_(q)CO₂H, (CH₂)_(q)COR³,(CH₂)_(q)SO₂NR¹¹R¹², (CH₂)_(q)NR¹¹SO₂R¹⁰, (CH₂)_(q)P(O)(OR⁸)(OR⁹),(CH₂)_(q)—O—(CH₂)_(p)CO₂H, (CH₂)_(q)—O—(CH₂)_(p)COR¹³,(CH₂)_(q)—O—(CH₂)_(p)P(O)(OR⁸)(OR⁹), (CH₂)_(q)—O—(CH₂)_(p)SO₂NR¹¹R¹², or(CH₂)_(q)—O—(CH₂)_(p)—NR¹¹SO₂R¹⁰; R⁸ and R⁹ are each independentlyhydrogen or (C₁-C₆)alkyl; and wherein G¹ and G² for each occurrence areeach independently hydrogen, (C₁-C₆)alkyl optionally independentlysubstituted with one or more halo, (C₁-C₈)alkoxy(C₁-C₆)alkyl or(C₃-C₈)cycloalkyl, or G¹ and G² together with the nitrogen to which theyare attached form a saturated heterocyclic ring having from 3 to 7carbon atoms wherein one of said carbon atoms may optionally be replacedby oxygen, nitrogen or sulfur; G³ for each occurrence is independentlyhydrogen or (C₁-C₆)alkyl; R¹⁰ for each occurrence is independently(C₁-C₆)alkyl or (C₁-C₆)alkoxy(C₁-C₆)alkyl; R¹¹ and R¹² are takenseparately and, for each occurrence, are independently hydrogen,(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, or (C₁-C₆)alkoxy(C₁-C₆)alkyl, or R¹¹and R¹² are taken together with the nitrogen atom to which they areattached and form a pyrrolidine, piperidine or morpholine ring whereinsaid pyrrolidine, piperidine or morpholine may optionally be substitutedat any carbon atom by (C₁-C₄)alkyl or (C₁-C₄)alkoxy; R¹³ for eachoccurrence is independently hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,NR¹¹R¹², (C₃-C₈)cycloalkyl, or (C₁-C₆)alkoxy(C₁-C₆)alkyl wherein R¹¹ andR¹² are as defined above; R¹⁴ and R¹⁵ are each independently hydrogen,halo, (C₁-C₆)alkyl, nitro, cyano, trifluoromethyl, SO₂R¹⁰, SO₂NR¹¹R¹²,NR¹¹R¹², COR¹³, CO₂R¹¹, (C₁-C₆)alkoxy, NR¹¹SO₂R¹⁰, NR¹¹COR¹³, NR¹¹CO₂R¹¹or OR¹¹; p for each occurrence is independently an integer of 1 to 6;and q for each occurrence is independently 0 or an integer of 1 to 6;with the proviso that when Q⁹ is O or S then n is not 0; with theproviso that when Q¹ is oxygen or sulfur then Q³ is absent; and with theproviso that when Q² is nitrogen then Q⁵ is absent; comprising (a)reacting the compound of a formula

wherein R¹ is hydrogen or halo, and n, R¹, R², R³ and X are as definedabove, with an amine of the formula H₂NY, wherein Y is as defined above,in the presence of N,N-diisopropylethylamine; (b) reacting the compoundof the formula VII so formed

wherein R¹ is hydrogen or halo, and wherein n, R² and Y are as definedabove with an organic acid anhydride, a dicarbonate or an organic acidchloride to form a compound of the formula

wherein n, R¹, R², R⁶ and Y are as defined above and (c) reacting thecompound of formula VI, wherein R¹ is halo, so formed with ammoniumformate in the presence of palladium-on-carbon.
 29. A process forpreparing a compound of the formula

wherein n is 0, 1, 2 or 3; R¹ is hydrogen or halo; each R² isindependently hydrogen, halo, trifluoromethyl, cyano, SR⁴, OR⁴, SO₂R⁴,OCOR⁵, or (C₁-C₁₀)alkyl wherein the alkyl group is optionallysubstituted by hydroxy, halo, cyano, N(R⁴)₂, SR⁴, trifluoromethyl, OR⁴,(C₃-C₈)cycloalkyl, (C₆-C₁₀)aryl, NR⁴COR⁵, COR⁵, SO₂R⁵, OCOR⁵, NR⁴SO₂R⁵and NR⁴CO₂ R⁴; R⁴ and R⁵, for each occurrence, are each independentlyselected from hydrogen, (C₁-C₁₀)alkyl, (C₁-C₁₀)alkoxy,(C₃-C₈)cycloalkyl,(C₆-C₁₀)aryl, (C₂-C₉)heterocycloalkyl,(C₂-C₉)heteroaryl or (C₁-C₆)aryl wherein the alkyl group is optionallysubstituted by the group consisting of hydroxy, halo, carboxy,(C₁-C₁₀)alkyl-CO₂, (C₁-C₁₀)alkylsulfonyl, (C₃-C₈)cycloalkyl,(C₁-C₁₀)alkoxy, or (C₁-C₆)alkyl; and wherein the aryl, heterocycloalkyland heteroaryl groups are optionally substituted by one to four groupsconsisting of halo, nitro, oxo, ((C₁-C₆)alkyl)₂amino, pyrrolidine,piperidine, (C₁-C₁₀)alkyl, (C₁-C₁₀)alkoxy, (C₁-C₁₀)alkylthio and(C₁-C₁₀)alkyl wherein the alkyl group is optionally substituted by oneto four groups selected from hydroxy, halo, carboxy, (C₁-C₆)alkyl-CO₂,(C₁-C₆)alkylsulfonyl, (C₃-C₈)cycloalkyl and (C₁-C₆)alkoxy; or R⁵ isN(R⁴)₂ wherein R⁴ is as defined above; comprising reacting the compoundof the formula

wherein n, R¹, R² and X are as defined above, with a non-nucleophilicbase.
 30. A process according to claim 29, wherein the non-nucleophilicbase is sodium hydroxide, potassium hydroxide, sodium hydride, potassiumtert-butoxide or 1,8-diazabicyclo[5.4.0]undec-7-ene.
 31. A compound ofthe formula

wherein n is 0, 1, 2 or 3; R¹ is hydrogen or halo; each R² isindependently hydrogen, halo, trifluoromethyl, cyano, SR⁴, OR⁴, SO₂R⁴,OCOR⁵, or (C₁-C₁₀)alkyl wherein the alkyl group is optionallysubstituted by hydroxy, halo, cyano, N(R⁴)₂, SR⁴, trifluoromethyl, OR⁴,(C₃-C₈)cycloalkyl, (C₆-C₁₀)aryl, NR⁴COR⁵, COR⁵, SO₂R⁵, OCOR⁵, NR⁴SO₂R⁵and NR⁴CO₂ R⁴; R⁴ and R⁵, for each occurrence, are each independentlyselected from hydrogen, (C₁-C₁₀)alkyl, (C₁-C₁₀)alkoxy,(C₃-C₈)cycloalkyl,(C₆-C₁₀)aryl, (C₂-C₉)heterocycloalkyl,(C₂-C₉)heteroaryl or (C₁-C₆)aryl wherein the alkyl group is optionallysubstituted by the group consisting of hydroxy, halo, carboxy,(C₁-C₁₀)alkyl-CO₂, (C₁-C₁₀)alkylsulfonyl, (C₃-C₈)cycloalkyl,(C₁-C₁₀)alkoxy, or (C₁-C₆)alkyl; and wherein the aryl, heterocycloalkyland heteroaryl groups are optionally substituted by one to four groupsconsisting of halo, nitro, oxo, ((C₁-C₆)alkyl)₂amino, pyrrolidine,piperidine, (C₁-C₁₀)alkyl, (C₁-C₁₀)alkoxy, (C₁-C₁₀)alkylthio and(C₁-C₁₀)alkyl wherein the alkyl group is optionally substituted by oneto four groups selected from hydroxy, halo, carboxy, (C₁-C₆)alkyl-CO₂,(C₁-C₆)alkylsulfonyl, (C₃-C₈)cycloalkyl and (C₁-C₆)alkoxy; or R⁵ isN(R⁴)₂ wherein R⁴ is as defined above.
 32. A compound according to claim31, wherein the compound of formula XI is the R enantiomer

wherein R¹ is chloro and R² is hydrogen.
 33. A compound according toclaim 31, wherein the compound of formula XI is the R enantiomer

wherein R¹ and R² are hydrogen.
 34. A compound of the formula

wherein n is 0, 1, 2 or 3; R¹ is hydrogen or halo; each R² isindependently hydrogen, halo, trifluoromethyl, cyano, SR⁴, OR⁴, SO₂R⁴,OCOR⁵, or (C₁-C₁₀)alkyl wherein the alkyl group is optionallysubstituted by hydroxy, halo, cyano, N(R⁴)₂, SR⁴, trifluoromethyl, OR⁴,(C₃-C₈)cycloalkyl, (C₆-C₁₀)aryl, NR⁴COR⁵, COR⁵, SO₂R⁵, OCOR⁵, NR⁴SO₂R⁵and NR⁴CO₂ R⁴; R⁴ and R⁵, for each occurrence, are each independentlyselected from hydrogen, (C₁-C₁₀)alkyl, (C₁-C₁₀)alkoxy,(C₃-C₈)cycloalkyl,(C₆-C₁₀)aryl, (C₂-C₉)heterocycloalkyl,(C₂-C₉)heteroaryl or (C₁-C₆)aryl wherein the alkyl group is optionallysubstituted by the group consisting of hydroxy, halo, carboxy,(C₁-C₁₀)alkyl-CO₂, (C₁-C₁₀)alkylsulfonyl, (C₃-C₈)cycloalkyl,(C₁-C₁₀)alkoxy, or (C₁-C₆)alkyl; and wherein the aryl, heterocycloalkyland heteroaryl groups are optionally substituted by one to four groupsconsisting of halo, nitro, oxo, ((C₁-C₆)alkyl)₂amino, pyrrolidine,piperidine, (C₁-C₁₀)alkyl, (C₁-C₁₀)alkoxy, (C₁-C₁₀)alkylthio and(C₁-C₁₀)alkyl wherein the alkyl group is optionally substituted by oneto four groups selected from hydroxy, halo, carboxy, (C₁-C₆)alkyl-CO₂,(C₁-C₆)alkylsulfonyl, (C₃-C₈)cycloalkyl and (C₁-C₆)alkoxy; or R⁵ isN(R⁴)₂ wherein R⁴ is as defined above.
 35. A compound according to claim34, wherein the compound of formula XI is the R enantiomer

wherein R¹ is chloro and R² is hydrogen.
 36. A compound according toclaim 34, wherein the compound of formula XI is the R enantiomer

wherein R¹ and R² are hydrogen.
 37. A compound of the formula

wherein n is 0, 1, 2 or 3; R¹ is hydrogen or halo; each R² isindependently hydrogen, halo, trifluoromethyl, cyano, SR⁴, OR⁴, SO₂R⁴,OCOR⁵, or (C₁-C₁₀)alkyl wherein the alkyl group is optionallysubstituted by hydroxy, halo, cyano, N(R⁴)₂, SR⁴, trifluoromethyl, OR⁴,(C₃-C₈)cycloalkyl, (C₆-C₁₀)aryl, NR⁴COR⁵, COR⁵, SO₂R⁵, OCOR⁵, NR⁴SO₂R⁵and NR⁴CO₂ R⁴; R³ is tetrahydrofuranyl, tetrahydropyranyl or a silylprotetcting group; X is halo, methanesulfonyloxy, benzenesulfonyloxy,p-toluenesulfonyloxy, m-nitrobenzenesulfonyloxy orp-nitrobenzenexulfonyloxy; R⁴ and R⁵, for each occurrence, are eachindependently selected from hydrogen, (C₁-C₁₀)alkyl,(C₁-C₁₀)alkoxy,(C₃-C₈)cycloalkyl,(C₆-C₁₀)aryl, (C₂-C₉)heterocycloalkyl,(C₂-C₉)heteroaryl or (C₁-C₆)aryl wherein the alkyl group is optionallysubstituted by the group consisting of hydroxy, halo, carboxy,(C₁-C₁₀)alkyl-CO₂, (C₁-C₁₀)alkylsulfonyl, (C₃-C₈)cycloalkyl,(C₁-C₁₀)alkoxy, or (C₁-C₆)alkyl; and wherein the aryl, heterocycloalkyland heteroaryl groups are optionally substituted by one to four groupsconsisting of halo, nitro, oxo, ((C₁-C₆)alkyl)₂amino, pyrrolidine,piperidine, (C₁-C₁₀)alkyl, (C₁-C₁₀)alkoxy, (C₁-C₁₀)alkylthio and(C₁-C₁₀)alkyl wherein the alkyl group is optionally substituted by oneto four groups selected from hydroxy, halo, carboxy, (C₁-C₆)alkyl-CO₂,(C₁-C₆)alkylsulfonyl, (C₃-C₈)cycloalkyl and (C₁-C₆)alkoxy; or R⁵ isN(R⁴)₂ wherein R⁴ is as defined above.
 38. A compound according to claim37, wherein the compound of formula IX is the R enantiomer

wherein R¹ is chloro; R² is hydrogen; R³ is tert-butyldimethylsilyl; andX is p-toluenesulfonyloxy.
 39. A compound according to claim 37, whereinthe compound of formula IX is the R enantiomer

wherein R¹ and R² are hydrogen.
 40. A compound of the formula

wherein n is 0, 1, 2 or 3; m is 1 or 2; R¹ is hydrogen or halo; each R²is independently hydrogen, nitro, halo, trifluoromethyl, cyano, SR⁴,OR⁴, SO₂R⁴, OCOR⁵, or (C₁-C₁₀)alkyl wherein the alkyl group isoptionally substituted by hydroxy, halo, cyano, N(R⁴)₂, SR⁴,trifluoromethyl, OR⁴, (C₃-C₈)cycloalkyl, (C₆-C₁₀)aryl, NR⁴COR⁵, COR⁵,SO₂R⁵, OCOR⁵, NR⁴SO₂R⁵ and NR⁴CO₂ R⁴; R⁴ and R⁵, for each occurrence,are each independently selected from hydrogen, (C₁-C₁₀)alkyl,(C₁-C₁₀)alkoxy, (C₃-C₈)cycloalkyl,(C₆-C₁₀)aryl, (C₂-C₉)heterocycloalkyl,(C₂-C₉)heteroaryl or (C₁-C₆)aryl wherein the alkyl group is optionallysubstituted by the group consisting of hydroxy, halo, carboxy,(C₁-C₁₀)alkyl-CO₂, (C₁-C₁₀)alkylsulfonyl, (C₃-C₈)cycloalkyl,(C₁-C₁₀)alkoxy, or (C₁-C₆)alkyl; and wherein the aryl, heterocycloalkyland heteroaryl groups are optionally substituted by one to four groupsconsisting of halo, nitro, oxo, ((C₁-C₆)alkyl)₂amino, pyrrolidine,piperidine, (C₁-C₁₀)alkyl, (C₁-C₁₀)alkoxy, (C₁-C₁₀)alkylthio and(C₁-C₁₀)alkyl wherein the alkyl group is optionally substituted by oneto four groups selected from hydroxy, halo, carboxy, (C₁-C₆)alkyl-CO₂,(C₁-C₆)alkylsulfonyl, (C₃-C₈)cycloalkyl and (C₁-C₆)alkoxy; or R⁵ isN(R⁴)₂ wherein R⁴ is as defined above.
 41. A compound according to claim40, wherein m is 2, R¹ is chloro, and R² is hydrogen.
 42. A compoundaccording to claim 40, wherein m is 2 and R² and R³ are hydrogen.
 43. Acompound according to claim 40, wherein the compound of formula XVII isthe R enantiomer

wherein m is 2 and R¹ and R² are hydrogen.
 44. A compound according toclaim 40, wherein the compound of formula XVII is the R enantiomer

wherein m is 2, R¹ is chloro and R² are hydrogen.
 45. A compound of theformula

wherein R¹ is hydrogen or chloro and BOC is tert-butoxycarbonyl.
 46. Acompound of the formula

wherein R¹ is hydrogen or chloro and BOC is tert-butoxycarbonyl.
 47. Acompound of the formula

wherein BOC is tert-butoxycarbonyl.
 48. A compound of the formula

wherein R¹ is hydrogen or halo.